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Vol. 56, Issue 3, 598-610, September 1999

Incorporation of the pi  Subunit into Functional gamma -Aminobutyric AcidA Receptors

Torben R. Neelands1 and Robert L. Macdonald

Neuroscience Program (T.R.N., R.L.M.) and Departments of Neurology (R.L.M.) and Physiology (R.L.M.), University of Michigan, Ann Arbor, Michigan

mRNA encoding the recently cloned gamma -aminobuytyric acidA receptor (GABAR) pi  subunit is expressed in the hippocampus and in several non-neuronal tissues including the uterus and ovaries. Whereas native GABARs are pentamers composed primarily of alpha beta gamma , alpha beta delta , or alpha beta epsilon subunits, it has not been demonstrated clearly that the pi  subunit incorporates into functional GABARs to form alpha beta pi receptors and, if so, with what properties. We provide electrophysiological evidence that the pi  subunit can coassemble with either alpha 5beta 3 or alpha 5beta 3gamma 3 subunits to produce recombinant GABARs with distinct pharmacological and biophysical properties. Compared with alpha 5beta 3 receptors, GABARs produced by coexpression of alpha 5beta 3pi subunits had a lower GABA EC50 value, were enhanced to a lesser extent by loreclezole, had different IC50 values for pregnenolone sulfate and lanthanum, and were insensitive to benzodiazepines. Incorporation of both pi  and gamma 3 subunits into an alpha 5beta 3gamma 3pi isoform was suggested by reduced enhancement by diazepam and a high zinc IC50 value. Current-voltage relations for the alpha 5beta 3pi subunit combination outwardly rectified more than currents from alpha 5beta 3gamma 3 but less than alpha 5beta 3 combination GABARs. Single-channel alpha 5beta 3 GABAR currents had a main conductance state of 15.2 picoSeimens (pS). Coexpression of the pi  subunit with alpha 5beta 3 subtypes increased the conductance level to 23.8 pS, similar to the conductance level of alpha 5beta 3gamma 3 GABARs (26.9 pS). We conclude that the pi  subunit coassembles with alpha , beta , and gamma  subunits to form functional alpha beta pi or alpha beta gamma pi GABARs and, thus, could have a significant impact on the function of native GABARs expressed in the brain or non-neuronal tissue.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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