Description:

The department of Physiology welcomes Simon Alford, Ph.D.

Abstract

Presynaptic Gi/o-coupled receptors cause decreased neurotransmission, an important control mechanism and I will argue, a critical component of synaptic integration. Mechanisms for fast membrane-delimited inhibition of secretion may work through voltage-dependent Ca2+channels (VDCCs). However, a direct interaction between Gβγ and SNARE proteins also inhibits exocytosis downstream of Ca2+ entry. This mechanism directly controls evoked release, leaving secondary effects of presynaptic Ca2+ unaffected, but also can modify components of exocytosis not available to mechanisms that control release probability. These include modifying neurotransmitter released by interacting with a region of the SNARE complex that controls fusion rate, and modifying spontaneous release. The same synapses have different Gi/o-GPCR-triggered modulation of neurotransmitter release by different mechanisms. In hippocampal neurons, GABAB receptors decrease calcium entry and 5HT1b receptors inhibit exocytosis by acting on SNAREs at the same synapse: this allows for presynaptic neural integration. Our understanding of the physiological role of Gβγ-SNARE interaction has lagged because of a lack of tools. But recent progress in understanding the molecular basis of this interaction, in particular a target for Gβγ on SNAP25 has yielded a transgenic SNAP25Δ3 mouse with a selectively disturbed Gβγ-SNARE interaction. This mouse has normal evoked exocytosis and normal inhibition of VDCC, but disturbed inhibition of exocytosis through Gβγ-SNARE interaction. This mouse provides clear evidence that the Gβγ-SNARE locus is physiologically important for regulation, because it has a number of interesting phenotypes both central and peripheral, including elevated stress-induced hyperthermia, impaired supraspinal nociception, defective spatial learning, impaired gait, and depressive-like behavior. Most interestingly, two-mediated inhibitory mechanisms, co-occurring at the same synapse, are synergistic. Thus, perhaps combinations of neurotransmitters may shape neuromodulation, giving rise to novel effects on circuits and presynaptic integration. It raises the possibility that therapeutic pairing of drugs that affect each mechanism may themselves work synergistically, an exciting possibility.