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== '''Introduction''' ==
== '''Introduction''' ==
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-Try to included methods of receptor functioning.... Mention AMPA receptors, Kainate receptors, NMDA receptors, with respect to glutamate regulation, also similarities of PCP and Ketamine. Make sure to mention the Mg2+ plug in the ionotropic pore of NMDA receptors... how disruption of the ionic flow/balance affects other receptors, and the synapse as a whole.
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The drug ketamine is used for medicinal purposes and also, because of its hallucinatory effects, used recreationally. Ketamine is classified as an NMDA receptor antagonist. When a neuron is stimulated, glutamate is released into the synapse and then binds to the NMDA receptor. This triggers the opening of the ion channel. However in the ionotropic pore there are magnesium ions, which greatly limits the ion flow. To counter this the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor also binds glutamate and flows freely. A voltage is built up by the flowing of sodium and potassium ions that eventually expels the magnesium, allowing for both sodium and calium ions to pass through. When ketamine binds to the NMDA receptor, the ion channel becomes plugged whether or not the magnesium is expelled, in particular blocking the flow of calcium. This means more AMPA receptors would be created, as well as Kainate receptors, which are also glutamate receptors that are not open as long. This effect has been known to cause problems with memory. In fact katamine and PCP, another NMDA receptor antagonist drug, were used to model the hypoglutamate state of schizophrenia. Today, ketamine is primarily used as a general anesthetic, but is also used as an analgesic and a bronchodilator to help breathing. It has even been proven effective in decreasing depression symptoms that accompany bipolar disorder. In knowing in greater detail the structure and function of both ketamine and the NMDA receptor, we can better understand the effects of ketamine and other similar drugs on the body both short and long term.
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(I can help you with this if you need me to)
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Anything that seems too involved, or not closely related enough we can start throwing into the additional information section. I haven't spoken with Justin, so I have no idea how that's going.
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[[Image:PCPMetabolism.png|thumb|PCP in reaction with heat.]]
[[Image:PCPMetabolism.png|thumb|PCP in reaction with heat.]]
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The NMDA Receptor primarily functions as a specific type of glutamate receptor. In addition to binding NMDA, its namesake, the receptor also contains binding sites for a wide variety of other molecules, most notably Benzodiazepines, D-serine, and Glycine. These binding sites occur extracellularly along the ligand binding domain (LBD). Glutamate binding alone is not enough to trigger a conformational change. In order to open the ion-channel, the NMDA receptor makes use of either Glycine or D-Serine, which are co-agonists. These two molecules comptete for the same binding site, and only their binding in conjunction with Glutamate can alter the protein's shape to expose the ion-channel. Furthermore, this allows the Mg2+ plug to be ejected from the pore during cellular depolarization-- the final stage before ion transport can begin.
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(Ligand Binding Domains vs Amino Terminal Domains)
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(Ketamine) -- Racemic properties, 4x stronger binding affinity for S-Ketamine (see image)
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(PCP) -- include discussion of metabolites, heat activated.... Blood-brain-barrier?
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(Mg2+)
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(Glutamate)
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Molecules such as Phencyclidine (PCP), Ketamine, and dizocilpine (MK-801) are known to block the flow of ions through the NMDA receptor. These molecules are non-competitive antagonists because they do not interfere with either the Glutamate or Glycine/D-Serine active sites. Instead, they bind to the ion-channel, similarly to magnesium. Given that the crystal structure of the ion-channel binding site has not yet been proven, it is difficult to pin down the roles of each residue in channel-blockage binding. However, there is evidence that the ideal binding site for these molecules occurs along side-chain oxygens of Asn 0 Residues, Phe and Leu at -1, Met +25, Val +28, and Ala +29. The pore itself is about 5.5 Angstroms in diameter which suggests the vast majority of blockers bind at the entrance to this very narrow section.
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(Glycine)
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As shown in figures 3 and 4, Ketamine and PCP both share similar cyclic carbon structures which can easily bind and block such a narrow opening. Ketamine itself has racemic properties, and it has been shown that (s)-Ketamine has a four-fold increase in binding affinity for the NMDA receptor. PCP has shown to have an even greater binding affinity, to the point where it causes severe damage to the protein structure through its inhibitory nature. Given that PCP is often smoked in recreational abuse, the heat causes a reaction that breaks the molecule down into 1-phenyl-1-cyclohexene (PC) and piperidine. PC is most likely the molecule that ultimate binds to the ion-channel, given it's close structural similarities to Ketamine.
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(D-Serine?)
{{STRUCTURE_3jpy | PDB=3jpy | SCENE= }}
{{STRUCTURE_3jpy | PDB=3jpy | SCENE= }}

Revision as of 07:33, 22 April 2011

This sandbox is in use until August 1, 2011 for UMass Chemistry 423. Others please do not edit this page. Thanks! Chem423 Team Projects: Understanding Drug Mechanisms

Group Members: Chris Brueckner, Daniel Roy, John Clarkson, Justin Srodulski

Template:STRUCTURE 1pbq

Contents

N-methyl-D-aspartate (NMDA) receptor in binding complex with Ketamine

Introduction

The drug ketamine is used for medicinal purposes and also, because of its hallucinatory effects, used recreationally. Ketamine is classified as an NMDA receptor antagonist. When a neuron is stimulated, glutamate is released into the synapse and then binds to the NMDA receptor. This triggers the opening of the ion channel. However in the ionotropic pore there are magnesium ions, which greatly limits the ion flow. To counter this the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor also binds glutamate and flows freely. A voltage is built up by the flowing of sodium and potassium ions that eventually expels the magnesium, allowing for both sodium and calium ions to pass through. When ketamine binds to the NMDA receptor, the ion channel becomes plugged whether or not the magnesium is expelled, in particular blocking the flow of calcium. This means more AMPA receptors would be created, as well as Kainate receptors, which are also glutamate receptors that are not open as long. This effect has been known to cause problems with memory. In fact katamine and PCP, another NMDA receptor antagonist drug, were used to model the hypoglutamate state of schizophrenia. Today, ketamine is primarily used as a general anesthetic, but is also used as an analgesic and a bronchodilator to help breathing. It has even been proven effective in decreasing depression symptoms that accompany bipolar disorder. In knowing in greater detail the structure and function of both ketamine and the NMDA receptor, we can better understand the effects of ketamine and other similar drugs on the body both short and long term.


-Chris

Overall Structure

To date, the entire X-ray or NMR crystal structure of the has not been produced. However, there are many structural subunits of NMDA that have successfully been crystallized and analyzed which provide some structural information about the NMDA receptor. The architecture of NMDA receptors is modular and is composed of multiple domains with distinct functional roles. The large extracellular region of the receptor is partitioned into two domains: an (ATD) and a (LBD) (7). Each domain consists of 8 and antiparallel . The alpha helices are located on the outside while the beta sheets are found more toward the center. The NMDA receptor has polar amino acid side-chains located extracellularly and at the ion-pore, but also many non-polar side chains at points where the protein passes through the phospholipid bilayer.

The ligand-binding domain of NMDA receptors are heterotetrameric ion channels composed of two copies of the glycine-binding NR1 subunit and two copies of the L-glutamate-binding NR2 subunit. The NR1 subunit is further divided up into splice units while the NR2 subunit has four sub-variants (NR2A-NR2D). The receptor as a whole has four general ligand binding sites (6).

The amino-terminal domain has an overall clamshell shaped structure and is notably distinct from non-NMDA receptor ATD's. The most important ATD is the NR2B ATD and it is particularly important in current research. It has been shown that the binding of Zn2+ provides neuroprotective agents without the adverse side effects that are more commonly observed with LBD agonists. NR2B ATD has the typical clamshell-like architecture composed of two domains, R1 and R2, which are tied together by three well-structured loops. There is a distinct R1–R2 domain orientation, which in NR2B ATD, is ‘twisted’ by a striking rotation of B45 and 541 compared with the R1–R2 orientation in GluR2 ATD or GluR6 ATD (7).

There are three types of sub units of an NMDA receptor, but not all receptors have the same composition of subtypes. Each subunit consists of three transmembrane segments, a P loop, and an intracellular C-terminus domain (CTD). The segments S1 and S2 in the LBD form a venus-flytrap structure and define the region for agonist recognition (6).

The first molecule is the open NMDA receptor in its natural state. The second is the closed NMDA receptor when it is bound by glutamate and co-agonist glycine. The third is the closed NMDA receptor when it is bound by Zn2+.

Template:STRUCTURE 2a5t

Drug Binding Site

Image:(S)Ketamine.png
S-Ketamine Structure
Image:PCPMetabolism.png
PCP in reaction with heat.

(Ligand Binding Domains vs Amino Terminal Domains)

(Ketamine) -- Racemic properties, 4x stronger binding affinity for S-Ketamine (see image)

(PCP) -- include discussion of metabolites, heat activated.... Blood-brain-barrier?

(Mg2+)

(Glutamate)

(Glycine)

(D-Serine?)

Template:STRUCTURE 3jpy

Additional Features

Credits

John Penis Clarkson: Introduction

Daniel Roy: Overall Structure

Chris Brueckner: Drug Binding Site

Justin Srodulksi: Additional Features


References

  1. test (PCP Metablite image)
  2. (Jerrold Meyer, Psychopharmacology textbook)
  3. (Biochem text book)
  4. (Ketamine-Induced NMDA Receptor Hypofunction as a Model of Memory Impairment and Psychosis)
  5. (The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia)
  6. http://chemwiki.ucdavis.edu/Wikitexts/Truman_Chem_421%3A_Nagan/N-Methyl-D-Aspartate_Receptor#Subunits
  7. Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit
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