Munc18‐1 as a key regulator of neurosecretion

Abstract

J. Neurochem. (2010) 115, 1–10. Abstract Munc18‐1 plays essential roles in neurosecretion by interacting with syntaxin‐1 and controlling the formation of the soluble N‐ethylmaleimide‐sensitive factor attachment protein receptors (SNARE) complex. At least three important functions of Munc18‐1 have been proposed: (i) molecular chaperone of syntaxin‐1 for appropriate localization and expression of syntaxin‐1, (ii) priming/stimulation of the SNARE‐mediated membrane fusion, and (iii) docking of large dense‐core vesicles to the plasma membrane. Similarly, at least two different binding modes have been proposed for the interaction between Munc18‐1 and syntaxin‐1: (i) binary binding to a ‘closed’ conformation of syntaxin‐1, and (ii) binding to the N‐terminal peptide of syntaxin‐1, which is thought to enable an interaction with the quaternary SNARE complex and/or further stabilize the binary interaction between Munc18‐1 and closed syntaxin‐1. Recent structural analyses have identified critical Munc18‐1 residues implicated in these different modes of binding. These have recently been tested functionally in rescue experiments using Munc18‐1 null neurons, chromaffin cells and Munc18‐1/‐2 knockdown PC12 cells, allowing remarkable progress to be made in the structural/functional understanding of Munc18‐1. In this review, we summarize these recent advances and attempt to propose an updated model of the pleiotropic functions of Munc18‐1 in neuroexocytosis.

Chaperoning of closed syntaxin-3 through Lys46 and Glu59 in domain 1 of Munc18 proteins is indispensable for mast cell exocytosis

“…The essential function of Munc18-1 in neuronal exocytosis (Verhage et al, 2000) is known to be mediated by its complex interactions with syntaxin-1 and/or the neuronal SNARE complex (Han et al, 2010). At least two important functions of Munc18-1 have been proposed: (1) priming of membrane fusion through direct interaction with the SNARE complex (Han et al, 2013;Han et al, 2014;Hu et al, 2010;Ma et al, 2013;Parisotto et al, 2014;Rodkey et al, 2008;Südhof and Rothman, 2009;Tareste et al, 2008;Xu et al, 2010); (2) molecular chaperone function of syntaxin-1 regulating appropriate intracellular localization and expression of syntaxin-1 (Arunachalam et al, 2008;Han et al, 2009;Malintan et al, 2009;McEwen and Kaplan, 2008;Medine et al, 2007;Rowe et al, 2001;Rowe et al, 1999;Shen et al, 2007).…”

The domain-3a of Munc18-1 plays a crucial role at the priming stage of exocytosis

“…Nevertheless, the precise modality of Munc18-1 contribution to exocytosis is still poorly understood. At least three important functions of Munc18-1 have been proposed (Han et al, 2010): (i) molecular chaperone of syntaxin-1, allowing proper localization and expression of syntaxin-1 (Arunachalam et al, 2008;Han et al, 2011;Han et al, 2009;Malintan et al, 2009;McEwen and Kaplan, 2008;Medine et al, 2007;Rowe et al, 2001;Rowe et al, 1999); (ii) priming via promotion of SNARE complex-mediated membrane fusion (Rodkey et al, 2008;Shen et al, 2007;Südhof and Rothman, 2009;Tareste et al, 2008); (iii) docking of large dense-core vesicles to the plasma membrane (Toonen et al, 2006;Voets et al, 2001).…”

A Pivotal Role for Pro-335 in Balancing the Dual Functions of Munc18-1 Domain-3a in Regulated Exocytosis

“…The precise modality of the contribution of Munc18-1 to exocytosis has been extensively studied in recent years through rescue assays with Munc18-1-deficient neurons (5,6), chromaffin cells (7) and Munc18-1/2 double knockdown neuroendocrine PC12 cells (8 -12), as well as through liposome fusion assays (13)(14)(15)(16)(17). At least two important functions of Munc18-1 have been proposed (18): (i) molecular chaperoning of syntaxin-1 allowing proper localization and expression of syntaxin-1 (8 -10, 19 -23); and (ii) priming or promoting SNARE complex-mediated membrane fusion (13,14,24,25). The former function is mediated primarily by the binding between the domain-1 cleft of Munc18-1 and "closed" syntaxin-1.…”