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.

The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids

“…8A ). In agreement with previous studies using STXBP-1/2 double-knockdown neurosecretory cells (Han et al, 2010 ; Han et al, 2009 ), DKO PC12 cells were also unable to secrete exogenous neuropeptide-Y (NPY) in response to depolarising stimulus in a NPY-human placental alkaline phosphatase (NPY-hPLAP) release assay (Appendix Fig. S6E ).…”

The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids

“…8A ). In agreement with previous studies using STXBP-1/2 double-knockdown neurosecretory cells (Han et al, 2010 ; Han et al, 2009 ), DKO PC12 cells were also unable to secrete exogenous neuropeptide-Y (NPY) in response to depolarising stimulus in a NPY-human placental alkaline phosphatase (NPY-hPLAP) release assay (Appendix Fig. S6E ).…”

Open syntaxin overcomes synaptic transmission defects in diverse C. elegans exocytosis mutants

“…Thus the observation that the open syntaxin mutation exacerbates rather than alleviates the Unc18 phenotypes can be rationalized by the impairment of the interaction of syntaxin with Unc18/Munc18-1 caused by this mutation. And a third reason is that anterograde trafficking of syntaxin/UNC-64 is known to be severely impaired in unc-18 mutants 21 , and similar defects have been demonstrated in Munc18-1/2 double knockdown PC12 cells 19, 20, 65, 66 as well as Munc18-1 KO neurons 22 . This trafficking defect is believed to be due to the formation of ectopic SNARE complexes in the ER and Golgi 67 .…”

Divisive normalization in mouse V1 is unchanged by increased thalamocortical short-term depression

“…2A). Stxbp1, also known as Munc18-1, is a presynaptic protein involved in synaptic vesicle release and recovery (Han et al, 2010;Stepien et al, 2019;Verhage et al, 2000;Voets et al, 2001), and its heterozygous deletion increases short-term depression without substantially affecting baseline transmission (Miyamoto et al, 2019a;Toonen et al, 2006). We found that increased short-term depression in white-matter inputs to layer 4 shortened visual responses in V1, but left contrast saturation and cross-orientation suppression unchanged.…”

The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids

“…8A ). In agreement with previous studies using STXBP-1/2 double-knockdown neurosecretory cells (Han et al, 2010 ; Han et al, 2009 ), DKO PC12 cells were also unable to secrete exogenous neuropeptide-Y (NPY) in response to depolarising stimulus in a NPY-human placental alkaline phosphatase (NPY-hPLAP) release assay (Appendix Fig. S6E ).…”

Open syntaxin overcomes synaptic transmission defects in diverse C. elegans exocytosis mutants

“…Thus the observation that the open syntaxin mutation exacerbates rather than alleviates the Unc18 phenotypes can be rationalized by the impairment of the interaction of syntaxin with Unc18/Munc18-1 caused by this mutation. And a third reason is that anterograde trafficking of syntaxin/UNC-64 is known to be severely impaired in unc-18 mutants 21 , and similar defects have been demonstrated in Munc18-1/2 double knockdown PC12 cells 19, 20, 65, 66 as well as Munc18-1 KO neurons 22 . This trafficking defect is believed to be due to the formation of ectopic SNARE complexes in the ER and Golgi 67 .…”

Divisive normalization in mouse V1 is unchanged by increased thalamocortical short-term depression

“…2A). Stxbp1, also known as Munc18-1, is a presynaptic protein involved in synaptic vesicle release and recovery (Han et al, 2010;Stepien et al, 2019;Verhage et al, 2000;Voets et al, 2001), and its heterozygous deletion increases short-term depression without substantially affecting baseline transmission (Miyamoto et al, 2019a;Toonen et al, 2006). We found that increased short-term depression in white-matter inputs to layer 4 shortened visual responses in V1, but left contrast saturation and cross-orientation suppression unchanged.…”

The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids

“…8A ). In agreement with previous studies using STXBP-1/2 double-knockdown neurosecretory cells (Han et al, 2010 ; Han et al, 2009 ), DKO PC12 cells were also unable to secrete exogenous neuropeptide-Y (NPY) in response to depolarising stimulus in a NPY-human placental alkaline phosphatase (NPY-hPLAP) release assay (Appendix Fig. S6E ).…”

Open syntaxin overcomes synaptic transmission defects in diverse C. elegans exocytosis mutants

“…Thus the observation that the open syntaxin mutation exacerbates rather than alleviates the Unc18 phenotypes can be rationalized by the impairment of the interaction of syntaxin with Unc18/Munc18-1 caused by this mutation. And a third reason is that anterograde trafficking of syntaxin/UNC-64 is known to be severely impaired in unc-18 mutants 21 , and similar defects have been demonstrated in Munc18-1/2 double knockdown PC12 cells 19, 20, 65, 66 as well as Munc18-1 KO neurons 22 . This trafficking defect is believed to be due to the formation of ectopic SNARE complexes in the ER and Golgi 67 .…”

Divisive normalization in mouse V1 is unchanged by increased thalamocortical short-term depression

“…2A). Stxbp1, also known as Munc18-1, is a presynaptic protein involved in synaptic vesicle release and recovery (Han et al, 2010;Stepien et al, 2019;Verhage et al, 2000;Voets et al, 2001), and its heterozygous deletion increases short-term depression without substantially affecting baseline transmission (Miyamoto et al, 2019a;Toonen et al, 2006). We found that increased short-term depression in white-matter inputs to layer 4 shortened visual responses in V1, but left contrast saturation and cross-orientation suppression unchanged.…”