NMDA receptor
| NMDA receptor | ||
|---|---|---|
| Secondary to quaternary structure | Heterotetramer | |
| Identifier | ||
| Gene name (s) | GRIN1 , GRIN2A , GRIN2B , GRIN2C , GRIN2D , GRIN3A , GRIN3B | |
| Transporter classification | ||
| TCDB | 1.A.10.1.6 | |
| designation | glutamate-gated ion channel | |
NMDA receptors are one of the ionotropic glutamate receptors . These are ion channels in the cell membrane that are activated by the binding of their ligand glutamate .
Surname
The name "NMDA receptor" comes from the fact that these receptors can be activated by binding the specific partial agonist N -methyl- D -aspartate (NMDA), which does not normally occur in the body, but in experiments just like the " Original agonist “glutamate leads to the opening of the ion channel subunit of the receptor.
function
Localized in the postsynaptic membrane , they control the flow of ions in the downstream nerve cell of the synapse in a non-selective manner for cations . The channel has different binding sites to which different ligands dock and thus control the receptor function. In a simplified way, ligands are to be understood as messenger substances that bind to certain binding sites on the receptor and cause changes in the structure of the receptor / channel, which ultimately influences the channel conductivity . In addition to the binding site for the actual messenger substance glutamate (which is thus referred to as an agonist) and a binding site for the coagonist glycine , the NMDA receptor shows binding sites for substances that reduce activity, so-called NMDA antagonists . A distinction is made between a binding site for competitive antagonists (e.g. CPP or APV ), binding sites for polyamines, protons and zinc ions, and a binding site for non-competitive antagonists . Dissociative drugs such as ketamine , PCP or MK-801 ( dizocilpin ) , for example, bind to this binding site inside the ion channel and act there as channel blockers .
Compared to AMPA receptors, NMDA receptors convey a slower postsynaptic current component, the duration of which is very long in the range of a few hundred milliseconds for synaptic connections. Their permeability to calcium in principal neurons is fifty times higher than that of the AMPA receptors. In contrast, however, is conductivity of NMDA receptors at negative membrane potentials (<-30 mV) is very low, because the channel with magnesium - ions is blocked.
A negative membrane potential , i.e. an excess of positively charged ions in the extracellular space compared to the interior of the cell, is called the resting membrane potential of an electrically excitable cell. Excited states are associated with a change in the electrical potential across the membrane; the numerical ratio of outside: inside positive or negative ions is locally limited to one another (depolarization). Only when the postsynaptic membrane is sufficiently depolarized do the NMDA receptors also contribute to the synaptic current. This property of being conductive only with simultaneous pre- and postsynaptic activity (especially for calcium) makes the NMDA receptors ideal molecular coincidence detectors. The simultaneous occurrence of both events (namely excited pre- and postsynaptic nerve cells) is not the rule and indicates that the corresponding synapse between two nerve cells is used particularly frequently. Today it is assumed that the increase in conductivity of the NMDA receptor is one of the essential elements for the induction of synaptic plasticity and thus represents a molecular mechanism for learning and memory .
The model says that NMDA receptors of certain synaptic pathways, which are used very frequently, are unblocked by the constant depolarization of the postsynaptic membrane and thus these pathways become more conductive than alternative interconnection patterns . Thus certain “paths” are paved , an essential process of learning. It can thus be understood that a pathological malfunction of the NMDA receptors is associated with the disease schizophrenia . An influencing (blockade) of NMDA receptors was also suspected for the so-called near-death experiences , because NMDA antagonists such as ketamine or phencyclidine can produce similar effects in some way.
Effect of alcohol on the NMDA receptor
If alcohol ( ethanol ) binds to the NMDA receptor, the influx of calcium ions is reduced. Thus, the frequency of excitatory potentials decreases, alcohol consequently reduces the effect of the most important excitatory system, while at the same time the function of the most important inhibitory system ( GABA ) is strengthened by binding to the GABA receptor . The alcohol-induced blockade of the NMDA receptor is associated, among other things, with memory disorders after excessive alcohol consumption. With excessive or long-term alcohol consumption, the number of NMDA receptors increases, while at the same time the influx of calcium increases. This counter-regulation leads to withdrawal symptoms during alcohol withdrawal, since the removal of the inhibition of the NMDA receptor leads to an overfunction of the excitatory system, which manifests itself in the form of restlessness, fear or insomnia.
NMDA receptor neurotoxicity (Olney's lesions)
When the substance group of the NMDA receptor antagonists was discovered, no harmful potential was initially known. It was not until John W. Olney et al. Showed in 1989 that the NMDA receptor antagonists dizocilpine, phencyclidine , ketamine and dextromethorphan , both orally and intravenously, cause lesions in the brains of rats. American dextromethorphan researcher William E. White said in his DXM FAQ in 1998 that he was convinced that NMDA receptor antagonists, also known as dissociatives , cause lesions in humans. However, he revoked this statement in 2003. A magnetic resonance tomographic examination of chronic ketamine users showed brain damage also in all 21 human test subjects, the number of lesions correlating with the duration of consumption.
See also
literature
- Jeremy M. Berg, John L. Tymoczko, Lubert Stryer : Biochemistry. 6th edition. Spectrum Akademischer Verlag, Heidelberg 2007, ISBN 978-3-8274-1800-5 .
- Donald Voet, Judith G. Voet: Biochemistry. 3. Edition. John Wiley & Sons, New York 2004, ISBN 0-471-19350-X .
- Bruce Alberts , Alexander Johnson, Peter Walter, Julian Lewis, Martin Raff, Keith Roberts: Molecular Biology of the Cell. 5th edition. Taylor & Francis, 2007, ISBN 978-0-8153-4106-2 .
Web links
- Overview of the structure and function of the NMDA receptor ( Memento from October 16, 2008 in the Internet Archive ), Bristol University (engl.)
Individual evidence
- ↑ Susanne Rösner: Meta-analysis on the effectiveness of acamprosate and naltrexone in the treatment of withdrawal from alcohol-dependent patients. (PDF) 2006, accessed December 15, 2014 .
- ↑ J. Olney, J. Labruyere, M. Price: Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs . In: Science . tape 244 , no. 4910 , 1989, pp. 1360-1362 , doi : 10.1126 / science.2660263 , PMID 2660263 .
- ↑ C. Anderson, The Bad News Isn't In: A Look at Dissociative-Induced Brain Damage and Cognitive Impairment. In: Erowid DXM Vaults: Health. June 1, 2003, accessed December 17, 2008 .
- ↑ Chunmei Wang, Dong Zheng, Jie Xu, Waiping Lam, DT Yew: Brain damages in ketamine addicts as revealed by magnetic resonance imaging . In: Frontiers in Neuroanatomy . tape 7 , 2013, doi : 10.3389 / fnana.2013.00023 ( frontiersin.org [accessed August 30, 2017]).