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Re: phasic vs. tonic inhibitory currents/psych med

Posted by B2chica on December 11, 2008, at 15:57:24

In reply to phasic vs. tonic inhibitory currents/psych med, posted by B2chica on December 11, 2008, at 13:10:56

Some interesting tidbits from an article.
"Receptors with Different Affinities Mediate Phasic and Tonic GABAA
Conductances in Hippocampal Neurons"
-the last paragraph you kind of have to sort through to get the good info from. but it wasn't clear unless i copied it all here.


"A nondesensitizing receptor with high affinity for GABA located extrasynaptically would be ideal for mediating tonic currents. It is therefore possible that different kinetics and binding affinities of the different subpopulations of GABAARs underlying tonic and phasic conductances cause them to respond differently when exposed to competitive antagonists."

"The binding mechanisms of agonists and competitive antagonists are fundamentally distinct (Jones et al., 2001) and have been shown to be unrelated for GABA and the competitive GABAAR antagonist SR95531 (gabazine) on _- and _-subunit-containing receptors (Wafford et al., 2001). Receptors containing either of these two mutually exclusive subunits (Araujo et al., 1998) have similar affinities for SR95531 (Wafford et al., 2001), but _-subunit containing receptors have a 50-fold higher affinity for GABA than _-subunit-containing receptors (Saxena and Macdonald, 1996).
Therefore, because of their different GABA affinities, a nonsaturating concentration of a competitive antagonist with the appropriate properties would more likely prevent GABA binding and thus block _-subunit-containing receptors to a greater extent than _-subunit-containing receptors. The Kon and Koff values for SR95531 are 4.28 _ 107 M-1 sec -1 and 9.1 sec_1, respectively (Jones et al., 1998), indicating that the binding affinity and off rate are sufficient to differentially affect high- and low-affinity GABAARs. If tonic inhibition recorded in dentate gyrus granule cells is primarily mediated by GABAARs with a higher affinity for GABA than receptors mediating phasic inhibition, then there should be a concentration of SR95531 that will barely block tonic inhibition but considerably antagonize phasic inhibition. Furthermore, very high concentrations of this antagonist should outcompete GABA at both receptors and completely block both conductances. We have previously demonstrated these predictions with a kinetic model of tonic and phasic inhibition using a nondesensitizing, high GABA-affinity receptor"



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poster:B2chica thread:868093
URL: http://www.dr-bob.org/babble/20081204/msgs/868130.html