The Short Splice Variant of the 2 Subunit Acts as an External Modulator of GABAA Receptor Function
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چکیده
GABAA receptors (GABAARs) regulate the majority of fast inhibition in the mammalian brain and are the target for multiple drug types, including sleep aids, anti-anxiety medication, anesthetics, alcohol, and neurosteroids. A variety of subunits, including the highly distributed 2, allow for pharmacologic and kinetic differences in particular brain regions. The two common splice variants 2S (short) and 2L (long) show different patterns of regional distribution both in adult brain and during the course of development, but show few notable differences when incorporated into pentameric receptors. However, results presented here show that the 2S variant can strongly affect both GABAAR pharmacology and kinetics by acting as an external modulator of fully formed receptors. Mutation of one serine residue can confer 2S-like properties to 2L subunits, and addition of a modified 2 N-terminal polypeptide to the cell surface recapitulates the pharmacological effect. Thus, rather than incorporation of a separate accessory protein as with voltage-gated channels, this is an example of an ion channel using a common subunit for dual purposes. The modified receptor properties conferred by accessory 2S have implications for understanding GABAAR pharmacology, receptor kinetics, stoichiometry, GABAergic signaling in the brain during development, and altered function in disease states such as epilepsy.
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تاریخ انتشار 2010