Acetylcholine

Acetylcholinesterase (EC 3.1.1.7, e.g. from Torpedo californica, TcAChE) hydrolysizes the neurotransmitter acetylcholine , producing group. ACh directly binds (via its nucleophilic Oγ atom) within the catalytic triad of (ACh/TcAChE structure 2ace). The residues are also important in the ligand recognition. After this binding acetylcholinesterase ACh.

Acetylcholine Receptors

Nicotinic acetylcholine receptors

• Nicotinic Acetylcholine Receptors in general

The receptor is a transmembrane pentameric glycoprotein. It cylindrical in appearance by electron microscopy approximately 16nm in length and 8nm in diameter. The main ion channel is composed of a water pore that runs through the entire length of the protein. If viewed from the synaptic cleft, the protein will look like a pseudo-symmetrical rosette shown in the picture below composed of 10 different alpha and 4 different beta subunits.

• .
• .
• .

• Alpha-bungarotoxin is a nicotinic cholinergic antagonist that is found within the venom of Bungarus multicinctus, a South-asian snake.
• Binding site of AChR
• Acetylcholine Receptor and its Reaction to Cobra Venom

When cobra venom is introduced into the body is moves along the bloodstream to a diaphragm muscle. It works as a postsynaptic neurotoxin binding to the receptor as an extracellular ligand by interacting with OH group leaving the acetylcholine channel open which releases ions used in creating an action potential. There must be 5 molecules of cobra toxin (red) to block the receptor (blue) as each molecule binds with an individual alpha chain on the acetylcholine receptor. The 2nd image depicts an individual toxin binding with one chain on the receptor, both in the same color. . This representation shows each molecule of the .

Muscarinic acetylcholine receptors

M1, M3, M5 receptors are coupled with G_q proteins, while M2 and M4 receptors are coupled with G_i/o proteins. They belong to GPCRs Subfamily A18.

• Muscarinic acetylcholine receptor

Acetylcholinesterase

• Acetylcholinesterase: Treatment of Alzheimer's disease
  
• Torpedo californica acetylcholinesterase with bifunctional inhibitor
  
• Acetylcholinesterase: Substrate Traffic and Inhibition
  
• Acetylcholinesterase Inhibitor Pharmacokinetics
  
• Acetylcholinesterase inhibitors
  
• AChE inhibitors and substrates
  
• Human Acetylcholinesterase
  
• African Malaria Mosquito Acetylcholinesterase
  
• Acetylcholinesterase inhibited by nerve agent soman
  
• Acetylcholinesterase with DFP
  
• Acetylcholinesterase with OTMA
  
• Acetylcholinesterase with acetylcholine
  
• Acetylcholinesterase complexed with N-9-(1',2',3',4'-tetrahydroacridinyl)-1,8-diaminooctane
  
• Complex of TcAChE with an iminium galanthamine derivative
  
• Complex of TcAChE with bis-acting galanthamine derivative
  
• Cholinesterase
  
• Flexibility of aromatic residues in acetylcholinesterase
  
• Huperzine A Complexed with Acetylcholinesterase & Huperzine A Complexed with Acetylcholinesterase (Chinese)
  
• Acetylcholinesterase complexed with Tacrine, the 1st anti Alzheimer's drug
  
• UMass Chem 423 Student Projects 2011-1: Acetylcholinesterase bound by Tacrine
• Torpedo Californica Acetylcholinesterase in complex with an (R)-Tacrine-(10)-Hupyridone inhibitor
  
• Torpedo Californica Acetylcholinesterase in complex with an (S)-Tacrine-(10)-Hupyridone inhibitor
  
• Torpedo californica acetylcholinesterase with alkylene-linked tacrine dimer (5 carbon linker)
  
• Torpedo californica acetylcholinesterase with alkylene-linked tacrine dimer (7 carbon linker)
  
• Torpedo californica acetylcholinesterase with bifunctional inhibitor
  
• Tetramerization domain of acetylcholinesterase
  
• African Malaria Mosquito Acetylcholinesterase
• Group:SMART:Acetylcholinesterase:A Story of Substrate Traffic and Inhibition by Green Mamba Snake Toxin
  
• Treatments:AChE Inhibitor References
  

Alzheimer's Disease

Adenosine

at Human A2A receptor.

Adenosine receptors

G_s → cAMP up

• Adenosine A2A receptor
• Effect of Caffeine (Trimethylxanthine) on Human A2A Receptor
• Adenosine A2A receptor 3D structures

Agonists:

• N6-3-methoxyl-4-hydroxybenzyl adenine riboside (B2)
• ATL-146e
• CGS-21680
• Regadenoson
• Adenosine

Antagonists:

• Caffeine
• aminophylline
• theophylline
• istradefylline
• SCH-58261
• SCH-442,416
• ZM-241,385

Adrenaline (Epinephrine)/Noradrenaline (Norepinephrine)

• .
• .
• Phenylethanolamine N-methyltransferase (Noradrenaline N-Methyltransferase) catalyzes the conversion of norepinephrine (noradrenaline) to epinephrine (adrenaline). This is the last step in the conversion of tyrosine to adrenaline^[1].

Adrenergic receptors in general

The adrenergic receptors are metabolic G protein-coupled receptors. They are the targets of catecholamines. The binding of an agonist to them causes a sympathetic response.

• The α-2 adrenergic receptor (A2AR) inhibits insulin or glucagons release.
  
• The β-1 adrenergic receptor (B1AR) increases cardiac output and secretion of rennin and ghrelin.^[2]
  
• The β-2 adrenergic receptor (B2AR) triggers many relaxation reactions.

β1 adrenergic receptor

• 3D structures in Adrenergic receptor.
• Beta-1 Adrenergic receptor
• G_s: adenylate cyclase activated, cAMP up.

• β1-adrenergic agonists:
  • Dobutamine, see Beta-1 Adrenergic receptor, 2y00, 2y01, 6h7l.
  • Isoprenaline, see Beta-1 Adrenergic receptor, 2y03.
  • Noradrenaline
  • Carmoterol, see 2y02.
  • Salbutamol (Albuterol in USA), 2y04.
• Beta blockers:
  • Metoprolol
  • Atenolol
  • Bisoprolol
  • Propranolol
  • Timolol
  • Nebivolol
  • Vortioxetine

β2 adrenergic receptor

• The human β2 adrenergic receptor bound to a G-protein (3sn6) is featured in a scene above, and additional structures are on the Adrenergic receptor page.
• Article Beta-2 Adrenergic Receptor by Wayne Decatur, David Canner, Dotan Shaniv, Joel L. Sussman, Michal Harel
• Article Beta-2 adrenergic receptor by Joel L. Sussman, Tala Curry, Michal Harel, Jaime Prilusky
• Group:SMART:A Physical Model of the beta-Adrenergic Receptor
• G_s: adenylate cyclase activated, cAMP up. For G_s see Beta2 adrenergic receptor-Gs protein complex updated.

β2-adrenergic agonists:

• • Salbutamol (Albuterol in USA)
  • Bitolterol mesylate
  • Formoterol
  • Isoprenaline
  • Levalbuterol
  • Metaproterenol
  • Salmeterol
  • Terbutaline
  • Ritodrine
• Beta blockers:
  • Butoxamine
  • Timolol
  • Propranolol
  • ICI-118,551
  • Paroxetine

Beta-adrenergic receptor kinase

Monoamine oxidases (MAO)

Monoamine oxidases (MAO) (EC 1.4.3.4) are a family of enzymes that catalyze the oxidation of monoamines including adrenaline, noradrenaline, serotonin and dopamine.

Monoamine oxidase

Monoamine oxidase b

Dopamine

DOPA decarboxylase

Dopamine Receptors

Dopamine receptors are a class of metabotropic G protein-coupled receptors that are important in the central nervous system. Dopamine receptors are involved in many neurological processes that comprise motivation, pleasure, cognition, memory, learning, and fine motor skills. There are five subtype dopamine receptors, D1, D2, D3, D4, and D5. The D3 receptor is a part of the D2-like family.^[3]

• Dopamine receptors 1 page
• Dopamine receptors 2 page

Agonists

• Amphetamine^[4]
• Methamphetamine^[5]

Antagonists

• Clebopride^[6]
• Nafadotride^[7]
• Eticlopride.

(3pbl).

.

Parkinson's disease

DOPA decarboxylase is responsible for the synthesis of dopamine and serotonin from L-DOPA and L-5-hydroxytryptophan, respectively. It is highly stereospecific, yet relatively nonspecific in terms of substrate, making it a somewhat uninteresting enzyme to study. Although it is not typically a rate-determining step of dopamine synthesis, the decarboxylation of L-DOPA to dopamine by DDC is the controlling step for individuals with Parkinson's disease^[8], the second most common neurodegenerative disorder, occuring in 1% of the population over the age of 65. The loss of dopaminergic neurons is the main cause of cognitive impairment and tremors observed in patients with the disease. The hallmark of the disease is the formation of alpha-synuclein containing Lewy bodies.

Currently, treatment for the disease is aimed at DOPA decarboxylase inhibition. Since dopamine cannot cross the blood-brain barrier, it cannot be used to directly treat Parkinson's disease. Thus, exogenously administered L-DOPA is the primary treatment for patients suffering from this neurodegenerative disease. Unfortunately, DOPA decarboxylase rapidly converts L-DOPA to dopamine in the blood stream, with only a small percentage reaching the brain. By inhibiting the enzyme, greater amounts of exogenously administered L-DOPA can reach the brain, where it can then be converted to dopamine. ^[9]. Unfortunately, with continued L-Dopa treatment, up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications (referred to as the "on-off phenomenon". ^[10]. Clearly, a better understanding of the catalytic mechanism and enzymatic activity of DDC in both healthy and PD individuals is critical to drug design and treatment of the disease.

GABA

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. (PDB code 4ms3).

• GABA receptor
• User:Rana Saad/The human GABAb receptor
• GABAA receptor

GABA(A) receptor-associated protein

Glutamate

Glutamate receptors

• .

Ionotropic Glutamate Receptors

Ionotropic Glutamate Receptors (IGluRs) are a family of ligand-gated ion channels that are responsible for fast excitatory neurotransmission.^[11] Primarily localized to nerve synapses in mammals, IGluRs are implicated in nearly all aspects of nervous system development and function.^[12] Synapses form the connection between two neuronal cells. Within synapses, neurotransmitters are released from vesicles in presynaptic cells and interact with receptors in postsynaptic cells to allow for communication between nerve cells.^[11] GluR domains include the amino terminal domain (ATD), transmembrane domain (TMD) and ligand-binding domain (LBD). Glutamate is the predominant neurotransmitter of excitatory synapses and interacts specifically with AMPA and NMDA IGluRs.

• AMPA receptor is a non-NMDA-type IGluR
  
• Kainate receptor (GluK) is a non-NMDA-type IGluR which is activated by the agonist kainate.
  
• NMDA receptor (NMDAR) is a IGluR which binds to the agonist NMDA. It contains subuntis NR1, NR2A, NR2B, NR2C, NR2D, NR3A, NR3B.
  
• Ionotropic Glutamate Receptors
• AMPA glutamate receptor

Full view of the glutamate receptor shows the overall structure (N-terminal, ligand-binding and transmembrane domains) in and models. is a part of the extracellular domain. This domain is implicated in receptor assembly, trafficking, and localization.

• .
• . This domain widens in response to glutamate binding allowing for positive ions to pass through the post-synaptic membrane.
• .
• .

• Glutamate receptor (GluA2)

Metabotropic Glutamate Receptors

Metabotropic glutamate receptors are glutamate receptors that activate ion channels indirectly through a signaling cascade involving G proteins^[13]. They are members of the large class of seven-transmembrane domain receptors, the G protein-coupled receptors. Glutamate receptors are classified into 3 groups based on their homology, mechanism and pharmacological properties.

• Metabotropic Glutamate Receptors
• Ligand Binding N-Terminal of Metabotropic Glutamate Receptors
• Metabotropic glutamate receptor 5

Histamine

.

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_q) that activates phospholipase C (see 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_q heterotrimeric G protein, the α-subunit of G_q 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
• 3rze - human histamine H1 receptor with an antagonist doxepin.

Neurotensin

• Neurotensin

Neurotensin receptors

The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as G protein-coupled receptors (GPCRs). Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of signal transduction.^[14] GPCRs are involved in a vast array of physiological processes within the body that range from interactions with dopamine to effects on secretion of bile in the intestines.^{[15] [16]} Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.^[17]

The ligand for NTSR1 is the 13 amino acid peptide, neurotensin (NTS)^[18], and the majority of the effects of NTS are mediated through NTSR1^[18]. NTS has a variety of biological activities including a role in the leptin signaling pathways ^[19], tumor growth ^[20], and dopamine regulation ^[21]. NTSR1 was crystallized bound with a C-terminal portion of its tridecapeptide ligand, . The shortened ligand was used because of oits higher potency and efficacy than its full-length counterpart^[18].

• Neurotensin receptor

Like other G protein-coupled receptors, NTSR1 is composed of 3 distinct regions. An where neurotensin binds and causes a conformational change of the protein. A region containing (PDB code: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 G-protein associated with this receptor.

The in NTSR1 is located at the top of the protein (Figure 1). NTSR1 also contains an allosteric , which is located directly beneath the ligand binding pocket and the two pockets, which are separated by the residue ^[22]. NTSR1 has been mutated to exist in both and states.

Serotonin

Serotonin receptors

5-hydroxytryptamine (5-HT), Serotonin receptors are found on the membrane of neurons in the central nervous system and peripheral nervous system. These receptors allow for the body to respond to serotonin and regulate many biological pathways. Serotonin, also known as 5 hydroxytryptamine, is an endogenous neurotransmitter made from tryptophan and is largely found in the gastrointestinal tract. It is known to regulate mood, appetite, digestion, circadian rhythm, learning and internal temperature regulation. It is can be an inhibitory or excitatory neurotransmitter that is released into the synaptic space and can bind to receptors on the postsynaptic neuron or be taken back up into the presynaptic neuron via Serotonin re-uptake transporters.^[23] 5-HT receptors are classified into 7 different subfamilies (5-HT1, 5-HT2, 5-HT3, etc.) by signaling mechanisms and homology of structure. All 5-HT receptors are known to have G-protein linked pathways except for the 5-HT3 receptor which acts as an ion channel. ^[24]

Serotonin receptors, main page

3D structures of Serotonin receptors

5-HT3A receptor

Serotonin Transporter

See also Serotonin N-acetyltransferase