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The Journal of Neuroscience, April 1, 2002, 22(7):2460-2468

G-Protein  Subunit Isoforms Couple Differentially to Receptors that Mediate Presynaptic Inhibition at Rat Hippocampal Synapses

Alex J. Straiker, Catherine R. Borden, and Jane M. Sullivan

The Salk Institute and the University of California, San Diego, La Jolla, California 92037

Presynaptic receptors that are coupled to heterotrimeric G-proteins are found throughout the brain and are responsible for modulating synaptic transmission. At least 10 G-protein-coupled receptors (GPCRs) reduce transmission in hippocampal neurons. Additionally, hippocampal neurons express up to 17 different G, G, and G subunits, making for a striking array of possible heterotrimer compositions and GPCR-heterotrimer interactions. The identity of the G subunit is likely a critical determinant in coupling specificity between GPCRs and their molecular effectors mediating presynaptic inhibition. We studied the role of four G_i/o subunits (G_o1, G_i1, G_i2, and G_i3) in mediating presynaptic inhibition in hippocampal neurons by expressing pertussis toxin-insensitive (PTx-ins) G_i/o mutants. PTx treatment of these cells disrupts coupling of endogenous subunits, leaving only the mutant G subunits to couple with native GPCRs and subunits. Successful rescue of presynaptic inhibition indicates that the expressed mutant G subunit can couple to the GPCR of interest. All four PTx-ins G subunits rescued presynaptic inhibition by adenosine A1 receptors. A PTx-ins G subunit also rescued adenosine A1-mediated inhibition of spontaneous vesicle fusion frequency. Of the remaining GPCRs tested, cannabinoid CB1, somatostatin, and GABA_B receptors displayed an  subunit-dependent selectivity in binding to G-protein heterotrimers, whereas group III metabotropic glutamate receptor-mediated inhibition was not rescued by expression of any of the four PTx-ins G subunits. Differential coupling of G-protein  subunits may be a means of achieving specificity between different GPCRs and their molecular targets for mediating presynaptic inhibition.

Key words: presynaptic inhibition; G-proteins; G-protein-coupled receptors; G subunit; coupling specificity; hippocampal neuron

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2272460-09$05.00/0

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