GTP-binding protein βγ subunits mediate presynaptic calcium current inhibition by GABA B receptor

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Abstract
A variety of GTP-binding protein (G protein)-coupled receptors are expressed at the nerve terminals of central synapses and play modulatory roles in transmitter release. At the calyx of Held, a rat auditory brainstem synapse, activation of presynaptic γ-aminobutyric acid type B receptors (GABA B receptors) or metabotropic glutamate receptors inhibits presynaptic P/Q-type Ca 2+ channel currents via activation of G proteins, thereby attenuating transmitter release. To identify the heterotrimeric G protein subunits involved in this presynaptic inhibition, we loaded G protein βγ subunits (Gβγ) directly into the calyceal nerve terminal through whole-cell patch pipettes. Gβγ slowed the activation of presynaptic Ca 2+ currents ( I pCa ) and attenuated its amplitude in a manner similar to the externally applied baclofen, a GABA B receptor agonist. The effects of both Gβγ and baclofen were relieved after strong depolarization of the nerve terminal. In addition, Gβγ partially occluded the inhibitory effect of baclofen on I pCa . In contrast, guanosine 5′- O -(3-thiotriphosphate)-bound G o α loaded into the calyx had no effect. Immunocytochemical examination revealed that the subtype of G proteins G o , but not the G i , subtype, is expressed in the calyceal nerve terminal. These results suggest that presynaptic inhibition mediated by G protein-coupled receptors occurs primarily by means of the direct interaction of G o βγ subunits with presynaptic Ca 2+ channels.