Neurotransmitters - Revision history

Alexander Berchansky at 12:35, 5 June 2023

2023-06-05T12:35:17Z

←Older revision		Revision as of 12:35, 5 June 2023
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	**Noradrenaline		**Noradrenaline
	**Carmoterol, see [[2y02]].		**Carmoterol, see [[2y02]].
-	**Salbutamol (Albuterol in USA), [[2y04]].	+	**[[Salbutamol]] (Albuterol in USA), [[2y04]].
	*Beta blockers:		*Beta blockers:
	**Metoprolol		**Metoprolol
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	*G<sub>s</sub>: adenylate cyclase activated, cAMP up. For G<sub>s</sub> see [[Beta2 adrenergic receptor-Gs protein complex updated]].		*G<sub>s</sub>: adenylate cyclase activated, cAMP up. For G<sub>s</sub> see [[Beta2 adrenergic receptor-Gs protein complex updated]].
	β2-adrenergic agonists:		β2-adrenergic agonists:
-	**Salbutamol (Albuterol in USA)	+	**[[Salbutamol]] (Albuterol in USA)
	**Bitolterol mesylate		**Bitolterol mesylate
	**[[Formoterol]]		**[[Formoterol]]

Alexander Berchansky at 10:05, 10 May 2023

2023-05-10T10:05:34Z

←Older revision		Revision as of 10:05, 10 May 2023
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	**Salbutamol (Albuterol in USA)		**Salbutamol (Albuterol in USA)
	**Bitolterol mesylate		**Bitolterol mesylate
-	**Formoterol	+	**[[Formoterol]]
	**Isoprenaline		**Isoprenaline
	**Levalbuterol		**Levalbuterol

Alexander Berchansky at 09:36, 2 March 2023

2023-03-02T09:36:51Z

←Older revision		Revision as of 09:36, 2 March 2023
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	**Levalbuterol		**Levalbuterol
	**Metaproterenol		**Metaproterenol
-	**Salmeterol	+	**[[Salmeterol]]
	**Terbutaline		**Terbutaline
	**Ritodrine		**Ritodrine

Alexander Berchansky at 15:07, 28 December 2021

2021-12-28T15:07:15Z

←Older revision		Revision as of 15:07, 28 December 2021
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	=GABA=		=GABA=
	==GABA receptors==		==GABA receptors==
-	'''GABA''' (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system. GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, '''GABAB receptors''' (metabotropic) utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from ~~'''~~GABAA receptors~~'''~~ (ionotropic), which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal.	+	'''GABA''' (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system. GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, '''GABAB receptors''' (metabotropic) utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from [[GABAA receptors]] (ionotropic), which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal.
	<scene name='82/829381/Cv/9'>GABA bound to the GABAB receptor</scene> (PDB code [[4ms3]]).		<scene name='82/829381/Cv/9'>GABA bound to the GABAB receptor</scene> (PDB code [[4ms3]]).
	*[[GABA receptor]]		*[[GABA receptor]]

Alexander Berchansky at 11:43, 16 November 2021

2021-11-16T11:43:30Z

←Older revision		Revision as of 11:43, 16 November 2021
Line 162:		Line 162:
	=GABA=		=GABA=
	==GABA receptors==		==GABA receptors==
-	'''GABA''' (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system. GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, '''GABAB receptors''' (metabotropic) utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from '''GABAA receptors''' (ionotropic), which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal.	+	'''GABA''' (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system. GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, '''GABAB receptors''' (metabotropic) utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from '''GABAA receptors''' (ionotropic), which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal.
	<scene name='82/829381/Cv/9'>GABA bound to the GABAB receptor</scene> (PDB code [[4ms3]]).		<scene name='82/829381/Cv/9'>GABA bound to the GABAB receptor</scene> (PDB code [[4ms3]]).
	*[[GABA receptor]]		*[[GABA receptor]]
	*[[User:Rana Saad/The human GABAb receptor]]		*[[User:Rana Saad/The human GABAb receptor]]
		+	*[[GABAA receptor]]
	==[[GABA(A) receptor-associated protein]]==		==[[GABA(A) receptor-associated protein]]==

Alexander Berchansky at 15:35, 21 October 2021

2021-10-21T15:35:42Z

←Older revision		Revision as of 15:35, 21 October 2021
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	<scene name='82/829381/Cv/5'>Histamine</scene>.		<scene name='82/829381/Cv/5'>Histamine</scene>.
	==Histamine receptors==		==Histamine receptors==
-	Allergy symptoms are mostly caused by the release of histamine in response to allergens. The binding of histamine to the extracellular portion of the H1 receptor triggers a structural change of the transmembrane portion, leading to a change in the C terminal area. This c terminal region interacts with G proteins, leading to the activation of the Gq signalling pathway, which triggers allergy symptoms like itchy eyes and runny noses. Many allergy drugs are anti-histamines, in that they bind to the histamine receptor but do not cause the conformational change that leads to a response. The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. The H1 receptor is linked to an intracellular G-protein (G<sub>q</sub>) that activates [[phospholipase C]] (see [[PLC beta 3 Gq\|Unique bidirectional interactions of Phospholipase C beta 3 with G alpha Q]] and the inositol triphosphate (IP3) signalling pathway. When a ligand binds to a G protein-coupled ~~receptorthat~~ is coupled to a G<sub>q</sub> heterotrimeric G protein, the α-subunit of G<sub>q</sub> can bind to and induce activity in the PLC isozyme PLC-β, which results in the cleavage of PIP2 into IP3 and DAG.	+	Allergy symptoms are mostly caused by the release of histamine in response to allergens. The binding of histamine to the extracellular portion of the H1 receptor triggers a structural change of the transmembrane portion, leading to a change in the C terminal area. This c terminal region interacts with G proteins, leading to the activation of the Gq signalling pathway, which triggers allergy symptoms like itchy eyes and runny noses. Many allergy drugs are anti-histamines, in that they bind to the histamine receptor but do not cause the conformational change that leads to a response. The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. The H1 receptor is linked to an intracellular G-protein (G<sub>q</sub>) that activates [[phospholipase C]] (see [[PLC beta 3 Gq\|Unique bidirectional interactions of Phospholipase C beta 3 with G alpha Q]] and the inositol triphosphate (IP3) signalling pathway. When a ligand binds to a G protein-coupled receptor that is coupled to a G<sub>q</sub> heterotrimeric G protein, the α-subunit of G<sub>q</sub> can bind to and induce activity in the PLC isozyme PLC-β, which results in the cleavage of PIP2 into IP3 and DAG.
	*[[Histamine H1 receptor]]		*[[Histamine H1 receptor]]
	* [[3rze]] - human histamine H1 receptor with an antagonist doxepin.		* [[3rze]] - human histamine H1 receptor with an antagonist doxepin.

Alexander Berchansky at 12:52, 27 July 2021

2021-07-27T12:52:36Z

←Older revision		Revision as of 12:52, 27 July 2021
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	The ligand for NTSR1 is the 13 amino acid peptide, neurotensin (NTS)<ref name="SONT">PMID:23051748</ref>, and the majority of the effects of NTS are mediated through NTSR1<ref name="SONT"/>. NTS has a variety of biological activities including a role in the '''[https://en.wikipedia.org/wiki/Leptin leptin]''' signaling pathways <ref name="Mice">PMID: 20211191</ref>, tumor growth <ref name="cancer">PMID:16887236</ref>, and '''[https://en.wikipedia.org/wiki/Dopamine dopamine]''' regulation <ref name="Schizophrenia">PMID:22596253</ref>. NTSR1 was crystallized bound with a C-terminal portion of its tridecapeptide '''[https://en.wikipedia.org/wiki/Ligand ligand]''', <scene name='72/721548/Neurotensin/7'>NTS(8-13)</scene>. The shortened ligand was used because of oits higher potency and efficacy than its full-length counterpart<ref name="SONT"/>.		The ligand for NTSR1 is the 13 amino acid peptide, neurotensin (NTS)<ref name="SONT">PMID:23051748</ref>, and the majority of the effects of NTS are mediated through NTSR1<ref name="SONT"/>. NTS has a variety of biological activities including a role in the '''[https://en.wikipedia.org/wiki/Leptin leptin]''' signaling pathways <ref name="Mice">PMID: 20211191</ref>, tumor growth <ref name="cancer">PMID:16887236</ref>, and '''[https://en.wikipedia.org/wiki/Dopamine dopamine]''' regulation <ref name="Schizophrenia">PMID:22596253</ref>. NTSR1 was crystallized bound with a C-terminal portion of its tridecapeptide '''[https://en.wikipedia.org/wiki/Ligand ligand]''', <scene name='72/721548/Neurotensin/7'>NTS(8-13)</scene>. The shortened ligand was used because of oits higher potency and efficacy than its full-length counterpart<ref name="SONT"/>.
-	[[Neurotensin receptor]]	+	*[[Neurotensin receptor]]
		+	Like other G protein-coupled receptors, NTSR1 is composed of 3 distinct regions. An <scene name='72/727765/Overall_structure/5'>extracellular binding site</scene> where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='73/733990/Overall/1'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G-protein] associated with this receptor.
		+
		+	The <scene name='72/721547/Hydrophobic_binding_pocket/6'>hydrophobic binding pocket</scene> in NTSR1 is located at the top of the protein (Figure 1). NTSR1 also contains an '''[https://en.wikipedia.org/wiki/Allosteric_regulation allosteric]''' <scene name='72/721548/Na_bind_pocket/13'>sodium binding pocket</scene>, which is located directly beneath the ligand binding pocket and the two pockets, which are separated by the residue <scene name='72/721548/Trp321/1'>Trp321</scene><ref name="SPGP">PMID:26205105</ref>. NTSR1 has been mutated to exist in both <scene name='72/721548/Ntsr1-elf/6'>active</scene> and <scene name='72/721547/Ntsr1-gw5/8'>active-like</scene> states.

	=Serotonin=		=Serotonin=

Alexander Berchansky at 12:47, 27 July 2021

2021-07-27T12:47:49Z

←Older revision		Revision as of 12:47, 27 July 2021
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	<scene name='82/829381/Cv/5'>Histamine</scene>.		<scene name='82/829381/Cv/5'>Histamine</scene>.
	==Histamine receptors==		==Histamine receptors==
-	Allergy symptoms are mostly caused by the release of histamine in response to allergens. The binding of histamine to the extracellular portion of the H1 receptor triggers a structural change of the transmembrane portion, leading to a change in the C terminal area. This c terminal region interacts with G proteins, leading to the activation of the Gq signalling pathway, which triggers allergy symptoms like itchy eyes and runny noses. Many allergy drugs are anti-histamines, in that they bind to the histamine receptor but do not cause the conformational change that leads to a response.	+	Allergy symptoms are mostly caused by the release of histamine in response to allergens. The binding of histamine to the extracellular portion of the H1 receptor triggers a structural change of the transmembrane portion, leading to a change in the C terminal area. This c terminal region interacts with G proteins, leading to the activation of the Gq signalling pathway, which triggers allergy symptoms like itchy eyes and runny noses. Many allergy drugs are anti-histamines, in that they bind to the histamine receptor but do not cause the conformational change that leads to a response. The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. The H1 receptor is linked to an intracellular G-protein (G<sub>q</sub>) that activates [[phospholipase C]] (see [[PLC beta 3 Gq\|Unique bidirectional interactions of Phospholipase C beta 3 with G alpha Q]] and the inositol triphosphate (IP3) signalling pathway. When a ligand binds to a G protein-coupled receptorthat is coupled to a G<sub>q</sub> heterotrimeric G protein, the α-subunit of G<sub>q</sub> can bind to and induce activity in the PLC isozyme PLC-β, which results in the cleavage of PIP2 into IP3 and DAG.
	*[[Histamine H1 receptor]]		*[[Histamine H1 receptor]]
		+	* [[3rze]] - human histamine H1 receptor with an antagonist doxepin.

	=Neurotensin=		=Neurotensin=

Alexander Berchansky at 14:12, 26 July 2021

2021-07-26T14:12:11Z

←Older revision		Revision as of 14:12, 26 July 2021
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-	'''Under construction!!!'''
	<StructureSection load='' size='400' side='right' scene='Acetylcholine/Cv/1' caption=''>		<StructureSection load='' size='400' side='right' scene='Acetylcholine/Cv/1' caption=''>
	=Acetylcholine=		=Acetylcholine=
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	*'''NMDA receptor''' (NMDAR) is a IGluR which binds to the agonist NMDA. It contains subuntis NR1, NR2A, NR2B, NR2C, NR2D, NR3A, NR3B.<br />		*'''NMDA receptor''' (NMDAR) is a IGluR which binds to the agonist NMDA. It contains subuntis NR1, NR2A, NR2B, NR2C, NR2D, NR3A, NR3B.<br />
	*[[Ionotropic Glutamate Receptors]]		*[[Ionotropic Glutamate Receptors]]
-	*[[Molecular Playground/Glutamate Receptor\|AMPA glutamate receptor]] by [http://www.umass.edu/cbi/ University of Massachusetts Amherst Chemistry-Biology Interface Program] at UMass Amherst and on display at the [http://www.molecularplayground.org/ Molecular Playground].	+	*[[Molecular Playground/Glutamate Receptor\|AMPA glutamate receptor]]
	Full view of the glutamate receptor shows the overall structure (N-terminal, ligand-binding and transmembrane domains) in <scene name='User:Mariel_Feliciano/sandbox_1/Full_view_black_background/6'>ribbon</scene> and <scene name='User:Mariel_Feliciano/sandbox_1/Full_view_spacefill/2'>spacefilling</scene> models. <scene name='User:Mariel_Feliciano/sandbox_1/Amino_terminal_domains/2'>N-terminal domain</scene> is a part of the extracellular domain. This domain is implicated in receptor assembly, trafficking, and localization.		Full view of the glutamate receptor shows the overall structure (N-terminal, ligand-binding and transmembrane domains) in <scene name='User:Mariel_Feliciano/sandbox_1/Full_view_black_background/6'>ribbon</scene> and <scene name='User:Mariel_Feliciano/sandbox_1/Full_view_spacefill/2'>spacefilling</scene> models. <scene name='User:Mariel_Feliciano/sandbox_1/Amino_terminal_domains/2'>N-terminal domain</scene> is a part of the extracellular domain. This domain is implicated in receptor assembly, trafficking, and localization.
	*<scene name='Molecular_Playground/Glutamate_Receptor/Transmembrane_domains/5'>Transmembrane Domain</scene>.		*<scene name='Molecular_Playground/Glutamate_Receptor/Transmembrane_domains/5'>Transmembrane Domain</scene>.
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	*<scene name='Molecular_Playground/Glutamate_Receptor/Glu_antagoinist/2'>Receptor antagonist 2K200225 binding site</scene>.		*<scene name='Molecular_Playground/Glutamate_Receptor/Glu_antagoinist/2'>Receptor antagonist 2K200225 binding site</scene>.
	*<scene name='Molecular_Playground/Glutamate_Receptor/Glu_agonist_/2'>Glutamate binding site</scene>.		*<scene name='Molecular_Playground/Glutamate_Receptor/Glu_agonist_/2'>Glutamate binding site</scene>.
		+
	*[[Glutamate receptor (GluA2)]]		*[[Glutamate receptor (GluA2)]]
-	The homomeric rat GluA2 receptor <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2/1'>has 4 subunits</scene> arranged in a 'Y'-shape with the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Meas3kg2/1'> 'top' being about 3 times the width of the 'bottom'</scene>. This structure is a functional homotetramer of the AMPA-subtype; native ionotropic glutamate receptors are almost exclusively heterotetramers. {{Link Toggle FancyCartoonHighQualityView}}.
-
-	'''Domains'''
-	The subunits themselves are modular <ref>PMID: 7539962</ref>and the major domains are found in layers in the tetrameric structure.
-	*The 'top' layer is composed of the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atd_domain/4'>amino-terminal domain (ATD)</scene>
-	::This <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atd_gly/2'>extracellular domain is glycosylated</scene>.
-	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Lbd_domain/4'>The ligand-binding domain (LBD)</scene> participates directly in agonist/competitive antagonist binding, affects activation gating, and is the portion that forms the 'middle' layer.
-	::<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Lbd_zk1/2'>The competitive antagonist ZK200775 is bound to the LBD</scene> in the structure.
-	::The <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Zk1_zoom/1'>ZK200775, a phosphonate quinoxalinedione AMPA antagonist</scene><ref>PMID: 9724812</ref>, was studied as a treatment for stroke because it had demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers; however, in a multicenter, double-blind, randomized, placebo-controlled phase II trial, it was found to have significant sedative effects in patients with acute stroke which precludes its further development as a neuroprotective agent<ref>PMID: 16131799</ref>.
-	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Tmd_domain/2'>The transmembrane domain (TMD)</scene> is the portion that forms the membrane-spanning on the 'bottom' of the solved structure.
-	::To help give a better idea of how the glutamate receptor is oriented on the cell surface in the membrane lipid bilayer, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/3kg2opm_mem/11'>a slab representative of hydrophobic core of the lipid bilayer</scene> as calculated by the [http://opm.phar.umich.edu/protein.php?pdbid=3kg2 Orientations of Proteins in Membranes database] (University of Michigan, USA) is shown with the red patch of spheres indicating the boundary of the hydrophobic core closest to the outside of the cell and the dark blue patch of spheres indicating the boundary closest to the inside of the cell.
-	::[[Image:Opm_periplasmic_topology.gif]]
-	* The carboxy-terminal domain that plays a role in both receptor localization and regulation is not seen in the structure but would be below the transmembrane domain as it is cytoplasmic.
-
-	'''Domain swapping between the subunits and symmetry mismatch between the domains'''
-
-	*Unanticipated is the domain swapping and crossover that occurs between the subunits interactions. In order to discuss the remarkable swapping, it is best to <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2letter/4'>designate each subunit with a letter</scene>: <br>    '''<span style="color:forestgreen">A</span>'''       '''<span style="color:red">B</span>'''       '''<span style="color:cornflowerblue">C</span>'''        '''D'''
-
-	*Considering each chain, there is crossover as the pairs of subunits seen in the ATD are swapped in the LBD.
-	::In the ATD domain -
-	::*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Ab_in_atd/1'>Portions of the A and B subunits pair up</scene>.
-	::*And the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Cd_in_atd/2'>Portions of the C and D subunits form a pair</scene>.
-	::*While that is going on, in the ATD there is also inter-pair interactions mediated between <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Abcd_in_atd/2'>subunits B and D</scene>. Note this view really highlights the two-fold symmetry between the A-B and C-D pairs at the level of the ATD.
-	::In the LBD domain -
-	::*Whereas in the ATD domain A and B paired up, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Ad_in_lbd/3'>portions of the A and D subunits pair up</scene> in the LBD.
-	::*And the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Bc_in_lbd/1'>Portions of the B and C subunits form a pair</scene>.
-	::*While that is going on, in the LBD there is also extensive inter-pair interactions mediated between <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Abcd_in_lbd/6'>subunits A and C</scene>. Note this view highlights the two-fold symmetry between the A-D and B-C pairs at the level of the LBD. <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Abcd_in_lbdside/1'>Looking from the side helps in seeing the inter-pair interactions between A and C</scene>.
-	:The domain swapping can be observed from the side following the backbone of each chain as well: <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/1'>A chain</scene>, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/2'>B chain</scene>, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/3'>C chain</scene>, and <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/5'>D chain</scene>. And <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2letter/4'>all for comparison</scene>.
-
-	*The <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Tmd_domain_4fold/2'>symmetry is an overall four-fold for the TMD</scene>. Thus, remarkably, the symmetry switches from an overall two-fold symmetry for the ATD and LBD to four-fold for the TMD.
-
-	As a result of the swapping and symmetry mismatch, there is subunit non-equivalence; even though all the chains are the same chemically, there are 2 distinct conformations of the subunits. This means there are 2 matching pairs of subunits.
-	* <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Ac3kg2letter/1'>A is equivalent to C</scene>
-	* <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Bd3kg2letter/2'>B is equivalent to D</scene>
-	* <span style="color:forestgreen">Subunit '''A</span>''' is equivalent to <span style="color:cornflowerblue">Subunit '''C'''</span> (in the small structure window in this section). In the main window, a <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atocmorph/5' target='main2NDwindow'>morph showing the equivalency of the 2 subunits by rotating around the axis of their symmetry</scene>.
-	* <span style="color:red">Subunit '''B</span>''' is equivalent to Subunit '''D''' (in the small structure window in this section). In the main window, a <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Btodmorph/5' target='main2NDwindow'>morph showing the equivalency of the two subunits by rotating around the axis of their symmetry</scene>.
-
-	However, each of the subunit '''<span style="color:forestgreen">A</span>'''/<span style="color:cornflowerblue">'''C'''</span> group though is distinct from those of the <span style="color:red">'''B</span>'''/'''D''' group. Having established the two equivalent groups we can simplify the discussion of the relationship between the two pairs by focusing solely on comparing <span style="color:forestgreen">Subunit '''A'</span>''' and <span style="color:red">Subunit '''B</span>'''.<br>
-	The domains themselves stay relatively static between the two conformational forms, with the linkers in between and the resulting arrangement changing. This is best illustrated by superposition of the individual domains of <span style="color:forestgreen">Subunit '''A</span>''' and <span style="color:red">Subunit '''B</span>''':
-	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atdatobsuper/4' target='main2NDwindow'>Superposition of the ATD</scene>.
-	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Lbdatobsuper/2' target='main2NDwindow'>Superposition of the LBD</scene>.
-	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Tmdatobsuper/1' target='main2NDwindow'>Superposition of the TMD</scene>.
-
-	<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atobmorph/2' target='main2NDwindow'>Subunit A morphing into Subunit B best illustrates how portions, especially the linkers, of the protein change</scene> between the two conformational forms.<br>
-	{{Button Toggle AnimationOnPause}}
-	:The linkers are key; besides playing roles in domain swapping and resolving the symmetry mismatch, they are also responsible for relaying the modulation signals from the ATD to the other domains and signaling the conformational change of the LBD to control the opening and closing of the pore. Beyond the two conformations seen here though this particular structure ([[3kg2]]) of the receptor does not shed light on the transduction process.
-
-	'''Transmembrane domain architecture and the occluded pore'''
-
-	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmemlabeled/1' target='main2NDwindow'>Transmembrane segments M1 to M4 depicted in different colors to show the approximate 4-fold rotational symmetry of the entire ion channel domain.</scene>
-	::* '''<span style="color:coral">M1</span>'''
-	::* '''<span style="color:lightgreen">M2</span>'''
-	::* '''<span style="color:violet">M3</span>'''
-	::* '''<span style="color:lightskyblue">M4</span>'''
-
-	*The segments shown again, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmem/4' target='main2NDwindow'>this time parallel to the 4-fold axis</scene>.
-	::There is <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmemclosed/1'>no pore visible in the center</scene> consistent with the channel being in a closed state with the antagonist ZK200775 bound to the LBD.
-	::It is <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/M3_closed/3' target='main2NDwindow'>the tight helix crossing of specifically the M3 helices</scene> that occludes the channel. [BE PATIENT as a small surface is generated.]
-	::Note <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/M3_closed_top/1' target='main2NDwindow'>the differences between the conformations of the carboxy-termini ('top') of the subunit A/C and B/D M3 segments</scene>. This is in part is why the symmetry is only approximately four-fold and is one of the several intriguing observations in regard to symmetry for this macromolecule. In fact, the location of 2-fold symmetry at the ends of M3 is just above the portion that spans the membrane and is close to the last region of the structure that doesn't show four-fold symmetry as abruptly below this point everything is 4-fold symmetric.
-
-	*To better observe the contributions of each of the membrane segments to the subunit-subunit interactions, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Trans_surf/4' target='main2NDwindow'>the transmembrane domains of three subunits are shown in a surface representation with the segments M1-M4 of the fourth subunit shown as green cylinders</scene>. <nowiki>[</nowiki>Note: this scene generates a substantial surface which may take about a minute to calculate. Be patient.<nowiki>]</nowiki>
-	::Note that the M4 segment associates with the ion-channel core of an adjacent subunit.
-	:{{Link Toggle FancyCartoonHighQualityView}}.
-	*The TMD domain of the GluA2 receptor shares structural and sequence similarity with the pore region of the potassium (K+), as hinted at by earlier work<ref name ="pot1">PMID: 7539962</ref><ref name ="pot2">PMID: 7761417</ref><ref name ="pot3">PMID: 9525859</ref>. Here the pore region of ''Streptomyces lividans'' potassium channel ([[1bl8]])<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Gluvspottmd/4' target='main2NDwindow'> superposed with the TMD domain of GluA2</scene>, specifically the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Gluvspottmdm3/1' target='main2NDwindow'>inner helix of the K+ channel aligned with the M3 segment</scene>. The <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Gluvspottmdm1/2' target='main2NDwindow'>M1 segment of GluA2 also overlays well with the outer helix</scene> of the K+ channel even though these portions weren't even included in the calculation of the alignment seen here.

	===Metabotropic Glutamate Receptors===		===Metabotropic Glutamate Receptors===
Line 255:		Line 191:
	*[[Ligand Binding N-Terminal of Metabotropic Glutamate Receptors]]		*[[Ligand Binding N-Terminal of Metabotropic Glutamate Receptors]]
	*[[Metabotropic glutamate receptor 5]]		*[[Metabotropic glutamate receptor 5]]
-

	=Histamine=		=Histamine=

Alexander Berchansky at 14:06, 26 July 2021

2021-07-26T14:06:59Z

←Older revision		Revision as of 14:06, 26 July 2021
Line 178:		Line 178:
	*'''NMDA receptor''' (NMDAR) is a IGluR which binds to the agonist NMDA. It contains subuntis NR1, NR2A, NR2B, NR2C, NR2D, NR3A, NR3B.<br />		*'''NMDA receptor''' (NMDAR) is a IGluR which binds to the agonist NMDA. It contains subuntis NR1, NR2A, NR2B, NR2C, NR2D, NR3A, NR3B.<br />
	*[[Ionotropic Glutamate Receptors]]		*[[Ionotropic Glutamate Receptors]]
-	*[[Molecular Playground/Glutamate Receptor\|AMPA receptor]]	+	*[[Molecular Playground/Glutamate Receptor\|AMPA glutamate receptor]] by [http://www.umass.edu/cbi/ University of Massachusetts Amherst Chemistry-Biology Interface Program] at UMass Amherst and on display at the [http://www.molecularplayground.org/ Molecular Playground].
		+	Full view of the glutamate receptor shows the overall structure (N-terminal, ligand-binding and transmembrane domains) in <scene name='User:Mariel_Feliciano/sandbox_1/Full_view_black_background/6'>ribbon</scene> and <scene name='User:Mariel_Feliciano/sandbox_1/Full_view_spacefill/2'>spacefilling</scene> models. <scene name='User:Mariel_Feliciano/sandbox_1/Amino_terminal_domains/2'>N-terminal domain</scene> is a part of the extracellular domain. This domain is implicated in receptor assembly, trafficking, and localization.
		+	*<scene name='Molecular_Playground/Glutamate_Receptor/Transmembrane_domains/5'>Transmembrane Domain</scene>.
		+	*<scene name='Molecular_Playground/Glutamate_Receptor/Transmembrane_domains_pore2/1'>Transmembrane Domain, other representaion</scene>. This domain widens in response to glutamate binding allowing for positive ions to pass through the post-synaptic membrane.
		+	*<scene name='Molecular_Playground/Glutamate_Receptor/Glu_antagoinist/2'>Receptor antagonist 2K200225 binding site</scene>.
		+	*<scene name='Molecular_Playground/Glutamate_Receptor/Glu_agonist_/2'>Glutamate binding site</scene>.
	*[[Glutamate receptor (GluA2)]]		*[[Glutamate receptor (GluA2)]]
		+	The homomeric rat GluA2 receptor <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2/1'>has 4 subunits</scene> arranged in a 'Y'-shape with the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Meas3kg2/1'> 'top' being about 3 times the width of the 'bottom'</scene>. This structure is a functional homotetramer of the AMPA-subtype; native ionotropic glutamate receptors are almost exclusively heterotetramers. {{Link Toggle FancyCartoonHighQualityView}}.
		+
		+	'''Domains'''
		+	The subunits themselves are modular <ref>PMID: 7539962</ref>and the major domains are found in layers in the tetrameric structure.
		+	*The 'top' layer is composed of the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atd_domain/4'>amino-terminal domain (ATD)</scene>
		+	::This <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atd_gly/2'>extracellular domain is glycosylated</scene>.
		+	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Lbd_domain/4'>The ligand-binding domain (LBD)</scene> participates directly in agonist/competitive antagonist binding, affects activation gating, and is the portion that forms the 'middle' layer.
		+	::<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Lbd_zk1/2'>The competitive antagonist ZK200775 is bound to the LBD</scene> in the structure.
		+	::The <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Zk1_zoom/1'>ZK200775, a phosphonate quinoxalinedione AMPA antagonist</scene><ref>PMID: 9724812</ref>, was studied as a treatment for stroke because it had demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers; however, in a multicenter, double-blind, randomized, placebo-controlled phase II trial, it was found to have significant sedative effects in patients with acute stroke which precludes its further development as a neuroprotective agent<ref>PMID: 16131799</ref>.
		+	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Tmd_domain/2'>The transmembrane domain (TMD)</scene> is the portion that forms the membrane-spanning on the 'bottom' of the solved structure.
		+	::To help give a better idea of how the glutamate receptor is oriented on the cell surface in the membrane lipid bilayer, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/3kg2opm_mem/11'>a slab representative of hydrophobic core of the lipid bilayer</scene> as calculated by the [http://opm.phar.umich.edu/protein.php?pdbid=3kg2 Orientations of Proteins in Membranes database] (University of Michigan, USA) is shown with the red patch of spheres indicating the boundary of the hydrophobic core closest to the outside of the cell and the dark blue patch of spheres indicating the boundary closest to the inside of the cell.
		+	::[[Image:Opm_periplasmic_topology.gif]]
		+	* The carboxy-terminal domain that plays a role in both receptor localization and regulation is not seen in the structure but would be below the transmembrane domain as it is cytoplasmic.
		+
		+	'''Domain swapping between the subunits and symmetry mismatch between the domains'''
		+
		+	*Unanticipated is the domain swapping and crossover that occurs between the subunits interactions. In order to discuss the remarkable swapping, it is best to <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2letter/4'>designate each subunit with a letter</scene>: <br>    '''<span style="color:forestgreen">A</span>'''       '''<span style="color:red">B</span>'''       '''<span style="color:cornflowerblue">C</span>'''        '''D'''
		+
		+	*Considering each chain, there is crossover as the pairs of subunits seen in the ATD are swapped in the LBD.
		+	::In the ATD domain -
		+	::*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Ab_in_atd/1'>Portions of the A and B subunits pair up</scene>.
		+	::*And the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Cd_in_atd/2'>Portions of the C and D subunits form a pair</scene>.
		+	::*While that is going on, in the ATD there is also inter-pair interactions mediated between <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Abcd_in_atd/2'>subunits B and D</scene>. Note this view really highlights the two-fold symmetry between the A-B and C-D pairs at the level of the ATD.
		+	::In the LBD domain -
		+	::*Whereas in the ATD domain A and B paired up, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Ad_in_lbd/3'>portions of the A and D subunits pair up</scene> in the LBD.
		+	::*And the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Bc_in_lbd/1'>Portions of the B and C subunits form a pair</scene>.
		+	::*While that is going on, in the LBD there is also extensive inter-pair interactions mediated between <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Abcd_in_lbd/6'>subunits A and C</scene>. Note this view highlights the two-fold symmetry between the A-D and B-C pairs at the level of the LBD. <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Abcd_in_lbdside/1'>Looking from the side helps in seeing the inter-pair interactions between A and C</scene>.
		+	:The domain swapping can be observed from the side following the backbone of each chain as well: <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/1'>A chain</scene>, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/2'>B chain</scene>, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/3'>C chain</scene>, and <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/5'>D chain</scene>. And <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2letter/4'>all for comparison</scene>.
		+
		+	*The <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Tmd_domain_4fold/2'>symmetry is an overall four-fold for the TMD</scene>. Thus, remarkably, the symmetry switches from an overall two-fold symmetry for the ATD and LBD to four-fold for the TMD.
		+
		+	As a result of the swapping and symmetry mismatch, there is subunit non-equivalence; even though all the chains are the same chemically, there are 2 distinct conformations of the subunits. This means there are 2 matching pairs of subunits.
		+	* <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Ac3kg2letter/1'>A is equivalent to C</scene>
		+	* <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Bd3kg2letter/2'>B is equivalent to D</scene>
		+	* <span style="color:forestgreen">Subunit '''A</span>''' is equivalent to <span style="color:cornflowerblue">Subunit '''C'''</span> (in the small structure window in this section). In the main window, a <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atocmorph/5' target='main2NDwindow'>morph showing the equivalency of the 2 subunits by rotating around the axis of their symmetry</scene>.
		+	* <span style="color:red">Subunit '''B</span>''' is equivalent to Subunit '''D''' (in the small structure window in this section). In the main window, a <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Btodmorph/5' target='main2NDwindow'>morph showing the equivalency of the two subunits by rotating around the axis of their symmetry</scene>.
		+
		+	However, each of the subunit '''<span style="color:forestgreen">A</span>'''/<span style="color:cornflowerblue">'''C'''</span> group though is distinct from those of the <span style="color:red">'''B</span>'''/'''D''' group. Having established the two equivalent groups we can simplify the discussion of the relationship between the two pairs by focusing solely on comparing <span style="color:forestgreen">Subunit '''A'</span>''' and <span style="color:red">Subunit '''B</span>'''.<br>
		+	The domains themselves stay relatively static between the two conformational forms, with the linkers in between and the resulting arrangement changing. This is best illustrated by superposition of the individual domains of <span style="color:forestgreen">Subunit '''A</span>''' and <span style="color:red">Subunit '''B</span>''':
		+	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atdatobsuper/4' target='main2NDwindow'>Superposition of the ATD</scene>.
		+	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Lbdatobsuper/2' target='main2NDwindow'>Superposition of the LBD</scene>.
		+	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Tmdatobsuper/1' target='main2NDwindow'>Superposition of the TMD</scene>.
		+
		+	<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atobmorph/2' target='main2NDwindow'>Subunit A morphing into Subunit B best illustrates how portions, especially the linkers, of the protein change</scene> between the two conformational forms.<br>
		+	{{Button Toggle AnimationOnPause}}
		+	:The linkers are key; besides playing roles in domain swapping and resolving the symmetry mismatch, they are also responsible for relaying the modulation signals from the ATD to the other domains and signaling the conformational change of the LBD to control the opening and closing of the pore. Beyond the two conformations seen here though this particular structure ([[3kg2]]) of the receptor does not shed light on the transduction process.
		+
		+	'''Transmembrane domain architecture and the occluded pore'''
		+
		+	*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmemlabeled/1' target='main2NDwindow'>Transmembrane segments M1 to M4 depicted in different colors to show the approximate 4-fold rotational symmetry of the entire ion channel domain.</scene>
		+	::* '''<span style="color:coral">M1</span>'''
		+	::* '''<span style="color:lightgreen">M2</span>'''
		+	::* '''<span style="color:violet">M3</span>'''
		+	::* '''<span style="color:lightskyblue">M4</span>'''
		+
		+	*The segments shown again, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmem/4' target='main2NDwindow'>this time parallel to the 4-fold axis</scene>.
		+	::There is <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmemclosed/1'>no pore visible in the center</scene> consistent with the channel being in a closed state with the antagonist ZK200775 bound to the LBD.
		+	::It is <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/M3_closed/3' target='main2NDwindow'>the tight helix crossing of specifically the M3 helices</scene> that occludes the channel. [BE PATIENT as a small surface is generated.]
		+	::Note <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/M3_closed_top/1' target='main2NDwindow'>the differences between the conformations of the carboxy-termini ('top') of the subunit A/C and B/D M3 segments</scene>. This is in part is why the symmetry is only approximately four-fold and is one of the several intriguing observations in regard to symmetry for this macromolecule. In fact, the location of 2-fold symmetry at the ends of M3 is just above the portion that spans the membrane and is close to the last region of the structure that doesn't show four-fold symmetry as abruptly below this point everything is 4-fold symmetric.
		+
		+	*To better observe the contributions of each of the membrane segments to the subunit-subunit interactions, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Trans_surf/4' target='main2NDwindow'>the transmembrane domains of three subunits are shown in a surface representation with the segments M1-M4 of the fourth subunit shown as green cylinders</scene>. <nowiki>[</nowiki>Note: this scene generates a substantial surface which may take about a minute to calculate. Be patient.<nowiki>]</nowiki>
		+	::Note that the M4 segment associates with the ion-channel core of an adjacent subunit.
		+	:{{Link Toggle FancyCartoonHighQualityView}}.
		+	*The TMD domain of the GluA2 receptor shares structural and sequence similarity with the pore region of the potassium (K+), as hinted at by earlier work<ref name ="pot1">PMID: 7539962</ref><ref name ="pot2">PMID: 7761417</ref><ref name ="pot3">PMID: 9525859</ref>. Here the pore region of ''Streptomyces lividans'' potassium channel ([[1bl8]])<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Gluvspottmd/4' target='main2NDwindow'> superposed with the TMD domain of GluA2</scene>, specifically the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Gluvspottmdm3/1' target='main2NDwindow'>inner helix of the K+ channel aligned with the M3 segment</scene>. The <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Gluvspottmdm1/2' target='main2NDwindow'>M1 segment of GluA2 also overlays well with the outer helix</scene> of the K+ channel even though these portions weren't even included in the calculation of the alignment seen here.
		+
	===Metabotropic Glutamate Receptors===		===Metabotropic Glutamate Receptors===
	Metabotropic glutamate receptors are [[Glutamate Receptors\|glutamate receptors]] that activate ion channels indirectly through a signaling cascade involving G proteins<ref>PMID:20716669</ref>. They are members of the large class of seven-transmembrane domain receptors, the [[G protein-coupled receptor\|G protein-coupled receptors]]. Glutamate receptors are classified into 3 groups based on their homology, mechanism and pharmacological properties.		Metabotropic glutamate receptors are [[Glutamate Receptors\|glutamate receptors]] that activate ion channels indirectly through a signaling cascade involving G proteins<ref>PMID:20716669</ref>. They are members of the large class of seven-transmembrane domain receptors, the [[G protein-coupled receptor\|G protein-coupled receptors]]. Glutamate receptors are classified into 3 groups based on their homology, mechanism and pharmacological properties.