Typically, when I see basic neuroscience research characterizing presynaptic signaling and postsynaptic receptor responsiveness within one of the big 5 neural systems (glutamate, GABA, serotonin, dopamine, and norepinephrine) I skim it over and don’t usually retain much information. Today, however, the sexy title of one of these articles maintained my attention long enough for me to blog about it in Neury Thursday. West Coast neuroscientists utilized glycine and glutamate pharmacological agents to characterize the properties of NR1 and NR3 subunits of the NMDA receptor. What does the NMDA receptor look like? This.

ResearchBlogging.orgAs many of you know, glutamate binds to the NMDA receptor, stimulating calcium influxes into the neuron and activating molecular machinery (protein kinases, phosphatases, second messenger systems, transcription, translation), and eventually, causing a cell to respond differently, a hormone to release differently, and an animal to act differently. NMDA receptors and their subunits mediate the integration of light within the circadian timing system in order to maintain or shift its phase, amplitude, or period (of the endogenous rhythm).

Abnormalities of the NMDA receptor are also linked to alcoholism; during chronic alcohol use, the density of NMDA receptors increases to compensate for the fact that ethanol (the active ingredient in alcohol) is blocking glutamate signaling at these receptors. When someone stops abusing alcohol, the density of NMDA receptors don’t decrease, which unfortunately, leads to severe physiological withdrawal and eventually alcohol dependence. This occurs because these individuals are biologically encouraged to consume more alcohol to alleviate the glutamate-induced side effects only to feel even worse and worse and worse and worse. Hence, a vicious cycle of alcohol abuse and abstinence ensues.

In this study, the researchers applied a glycine agonist (D-serine) to the NR1 and NR3 NMDA receptor subunits resting on an intact optic nerve and characterized calcium activity using a “high-resolution calcium-imaging technique.” They found that glycine stimulated calcium release in NR1/NR3 subunits within myelin. What does that mean? It means that glycine agonists acting at NMDA receptors can control the speed of a neuronal message (that’s what myelin is for). Additionally, the researchers uncovered that the NR3 subunit was absolutely necessary for a glycine-induced calcium influx to occur because glycine-induced calcium influxes did not occur in animals without NR3 subunits (i.e. they were knocked-out). Even more interesting, treating the NR1/NR3 subunits with a glutamate antagonist did not stimulate calcium influxes in BOTH wild-type and knocked-out mice.

Certainly, characterizing the properties of these NMDA receptor subunits and what effects various neurotransmitters have on these receptors could yield more efficacious treatments currently available for the treatment of alcoholism such as naltexone and acamprosate. These novel NR1 and NR3 subunit treatments may even solve some of the limitations of naltrexone and acamprosate, such as a greater efficacy in Asian populations and reduced efficacy (i.e. tolerance) with continual use, respectively. Will there be a glycine-binding drug in the near future? Hopefully.
Juan C. Pin˜a-Crespo,1,2* Maria Talantova,2* Ileana Micu,5* Bradley States,2 H.-S. Vincent Chen,2,4 Shichun Tu,2, Nobuki Nakanishi,2 Gary Tong,2,3 Dongxian Zhang,2 Stephen F. Heinemann,1,3 Gerald W. Zamponi,6 Peter K. Stys,5, & and Stuart A. Lipton2,3 (2010). Excitatory Glycine Responses of CNS Myelin Mediated by
NR1/NR3 “NMDA” Receptor Subunits Journal of Neuroscience (34), 11501-11505 : DOI:10.1523/JNEUROSCI.1593-10.2010