Disease relevance of Stxbp1

• A pulsed KTP pumped dye laser (25 kHz repetition rate and 470 nsec pulse width) has been compared to a continuous wave argon ion pumped dye laser as the source of 630 nm light during in-vitro and in-vivo Photofrin-II mediated photosensitization studies [1].

High impact information on Stxbp1

• Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmitter secretion from synaptic vesicles throughout development [2].
• Calcium-dependent LDCV exocytosis was reduced 10-fold in mouse chromaffin cells lacking Munc18-1, but the kinetic properties of the remaining release, including single fusion events, were not different from controls [3].
• Munc18-1 promotes large dense-core vesicle docking [3].
• Moreover, acute overexpression of Munc18-1 in bovine chromaffin cells increased the amount of releasable vesicles and accelerated vesicle supply [3].
• To determine the role of n-Sec1/Munc-18 in neurotransmitter release in vivo, we have overexpressed the Drosophila homolog, rop, in third instar larvae and measured the electrophysiological consequences at the neuromuscular junction [4].

Biological context of Stxbp1

• The syntaxin binding protein 1 gene (Stxbp1) is a candidate for an ethanol preference drinking locus on mouse chromosome 2 [5].
• Regulation of exocytosis by cyclin-dependent kinase 5 via phosphorylation of Munc18 [6].
• Instead, the presence of SNARE complexes in the absence of membrane fusion in munc18-1 knockout mice indicates that Munc18-1 either controls the spatially correct assembly of core complexes for SNARE-dependent fusion, or acts as a direct component of the fusion machinery itself [7].
• Munc18-2 has a striking resemblance to Munc18-1 in structure despite only 60% sequence identity, suggesting a recent gene duplication event [8].
• These mammalian isoforms exhibit 58% (Munc-18-1) and 42-43% (Munc-18-3) amino acid sequence identity with UNC-18 [9].

Anatomical context of Stxbp1

• This implicates the existence of other mammalian Munc-18 homologues that may be involved in a range of vesicle transport reactions [10].
• Munc-18a is identical to Munc-18 and by Northern analysis is expressed predominantly in brain and to a lesser extent in testis and 3T3-L1 cells [10].
• We have previously identified three mammalian Sec1/Munc-18 homologues in adipocytes (Tellam, J. T., McIntosh, S., and James, D. E. (1995) J. Biol. Chem. 270, 5857-5863) [11].
• Expression of Munc13-1, along with its cognate partners, syntaxin 1a and Munc18a, is reduced in the pancreatic islets of type-2 diabetes non-obese Goto-Kakizaki and obese Zucker fa/fa rats [12].
• Here, we report on our investigation of the role of syntaxin-binding Munc18 isoforms and the microtubule network in this process [13].

Associations of Stxbp1 with chemical compounds

• The present study provides supporting evidence for the involvement of Stxbp1 in ethanol preference drinking [5].
• These data suggest that Munc-18-1 and C. elegans unc-18 may play positive roles in ACh release and that the molecular mechanism of neuronal regulated secretion has been partially conserved from nematodes to mammals [9].

Enzymatic interactions of Stxbp1

• We have now demonstrated that Cdk5 is capable of phosphorylating Munc18a in vitro within a preformed Munc18a.syntaxin 1a heterodimer complex and that this results in the disassembly of the complex [6].

Regulatory relationships of Stxbp1

• Tomosyn was previously identified as a syntaxin-binding protein that inhibits soluble NSF (n-ethylmaleimide-sensitive fusion protein) attachment protein receptor (SNARE)-mediated secretion [14].

Other interactions of Stxbp1

• Munc-18c is 51% identical to Munc-18 and is ubiquitously expressed [10].
• Munc-18b is 62% identical to Munc-18 at the amino acid level and is expressed in testis, intestine, kidney, rat adipose tissue, and 3T3-L1 cells [10].
• The enhanced secretion in mutant beta cells is correlated with a decrease in the formation of the fusion-incompetent syntaxin-1a-Munc18-1 complex, with which granuphilin normally interacts [15].
• As such, regulation of the interaction between Munc18a and syntaxin 1a may provide an important mechanism controlling secretory responsiveness [6].
• Three SM (Sec1/Munc18) proteins are present in mouse platelets (Munc18a, 18b and 18c) and each potentially regulates exocytosis via modulation of their cognate syntaxin binding partner [16].

Analytical, diagnostic and therapeutic context of Stxbp1

• Munc18a, Munc18b, and Munc18c were detected in human platelets by immunoblotting and/or PCR [17].
• I further show by immunoprecipitation and cotransfection assays that Munc18-1, but not syntaxin IA, directly interacts with the C-terminal domain of Slp4-a in a Rab27A-independent manner [18].
• Using site-directed mutagenesis, the Cdk5 phosphorylation site on Munc18a was identified as Thr574 [6].
• The N-sec-butyl S isomer 10a showed analgesia approximating morphine with nalorphine-like antagonist activity [19].

References