Activation of metabotropic GABA receptors increases the energy barrier for vesicle fusion

Abstract

Neurotransmitter release from presynaptic terminals is under the tight control of various metabotropic receptors. We report here that in addition to the regulation of Ca 2+ channel activity, metabotropic GABA B receptors (GABA BRs) at murine hippocampal glutamatergic synapses utilize an inhibitory pathway that directly targets the synaptic vesicle release machinery. Acute application of the GABA BR agonist baclofen rapidly and reversibly inhibits vesicle fusion, which occurs independently of the SNAP-25 C-terminus. Using applications of hypertonic sucrose solutions, we find that the size of the readily releasable pool remains unchanged by GABA BR activation, but the sensitivity of primed vesicles to hypertonic stimuli appears lowered as the response amplitudes at intermediate sucrose concentrations are smaller and release kinetics are slowed. These data show that presynaptic GABA BRs can inhibit neurotransmitter release directly by increasing the energy barrier for vesicle fusion. © 2011. Published by The Company of Biologists Ltd.