Molecular Controls on Regulated Neurotransmitter and Neurohormone Secretion

Abstract

The neurosecretion of chemical messengers via Ca²⁺-dependent exocytosis is fundamental to the survival of multicellular organisms and to the induction of physiological changes that may underlie learning and behavior. These processes involve ensembles of molecular interactions or ‘nanomachines’, which continuously modulate vesicle cycling and membrane fusion. The formation and disassembly of molecular complexes directing the secretory pathway principally define the (1) the number of exocytotic sites for release-ready vesicles at the plasma membrane; (2) the relative occupancy of the sites; (3) the probability of stimulus-dependent exocytotic release at each site; and (4) the degree to which renewal processes are engaged to support highly repetitive and/or sustained secretion. In this chapter, we focus on classes of proteins that have been considered “clamps” within the Ca²⁺-regulated release process.

Key References: See Main List for Reference Details

• Aligianis et al. (2005) This study is among a few that show severe neurodevelopmental phenotypes resulting from mutation or abrogation of regulators of Rab3/27 GTPases.

• Cazares et al. (2016) First evidence from mammalian neurons to indicate that Tomosyn generates a non-releasable pool of vesicles independent of its R-SNARE domain. These findings are parallel to those in yeast, where the Tomosyn ortholog, Sro7, shows similar phenotypes.

• Cheng et al. (2015) Discovery of the molecular mechanism underlying dissociation of Rab3 GTPases from vesicle membranes in an activity-dependent manner.

• Li et al. (2016) These studies provide evidence for a mechanism by which the temporal dynamics of SNARE zippering (seconds to minutes) can be reconciled with the observed timescales of vesicle pool refilling (hundreds of milliseconds). They find that the formation of trans-SNARE complexes can be significantly accelerated by molecular factors (i.e., Tomosyn).

• Müller et al. (2011) Using an electrophysiology based screen these studies identify that Rab3-GAP is a gatekeeper for induction and expression of homeostatic plasticity. Consistent with the action of clamps, they find that the function of Rab3-GAP appears necessary to relieve suppression of homeostatic plasticity that is catalyzed by Rab3 proteins.

• Park et al. (2017) This study is the most recent to present biochemical and in vivo data from C. elegans to significantly strengthen the idea that a conformational switch in UNC18-1 can confer either inhibitory or secretion enhancing action. Moreover, they also support the hypothesis that the enhancing actions of UNC18-1 are downstream of UNC13-1.

• Rossi et al. (2015) Yeast studies on Rab-GTPases and SNAREs have been leading the way in delineating the processes and molecules that bridge the vesicle targeting, priming, and fusion steps in living cells. The experiments in this article suggest a model by which the yeast ortholog of Tomosyn, Sro7, can switch between inhibitory modes leading to vesicles clustering or positive roles by catalyzing Rab-mediated vesicle tethering to SNARE assembly through a simple conformation change.

• Trimbuch and Rosenmund (2016) This perspective article clearly articulates how complexin acts as a clamp capable of enhancing or inhibiting neurosecretion by changing the energy barrier for fusion. Moreover, it proposes that its actions are species and even synapse specific.

• Xu et al. (2012) An elegant demonstration of how molecules capable of changing modes of neurotransmitter release can change learning capabilities. Critically, manipulation of Syt1 expression, and thus release mode, had distinct effects on learning in hippocampus vs. prefontal cortex.

• Yamamoto et al. (2010) In support of a model where Tomosyn proteins can switch between inhibitory and secretion enhancing roles, these studies suggest that PKA phosphorylation modifies the positioning of Tomosyn’s tail domain to relieve its inhibitory actions.