Received for publication September 16, 2005.
Revised November 22, 2005.
Accepted for publication December 20, 2005.

Endogenous RGS Proteins Regulate the Kinetics of Gq/11-Mediated Modulation of Ion Channels in CNS Neurons

Abstract

Slow synaptic potentials are generated when metabotropic G-protein coupled receptors activate heterotrimeric G-proteins, which in turn modulate ion channels. Many neurons generate excitatory postsynaptic potentials mediated by G-proteins of the G_q/11 family, which in turn activate phospholipase C-. Accessory GTPase activator proteins (GAPs) are thought to be required to accelerate GTP hydrolysis and rapidly turn off G-proteins, but the involvement of GAPs in neuronal G_q/11 signaling has not been examined. Here we show that Regulators of G-protein signaling (RGS proteins) provide necessary GAP activity at neuronal G_q/11 subunits. We reconstituted inhibition of native 2-pore domain potassium channels in cerebellar granule neurons by expressing chimeric G subunits that are activated by G_i/o-coupled receptors, thus bypassing endogenous G_q/11 subunits. RGS-insensitive (RGSi) variants of these chimeras mediated inhibition of potassium channels that developed and recovered more slowly than inhibition mediated by RGS-sensitive (wild-type) chimeras or native G_q/11 subunits. These changes were not accompanied by a change in agonist sensitivity, as might be expected if RGS proteins acted primarily as effector antagonists. The slowed recovery from potassium channel inhibition was largely reversed by an additional mutation that mimics the RGS-bound state. These results suggest that endogenous RGS proteins regulate the kinetics of rapid G_q/11-mediated signals in CNS neurons by providing GAP activity.

Key words: Gq/11 family, RGS proteins