Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform

Abstract

Munc13 proteins constitute a family of three highly homologous molecules (Munc13-1, Munc13-2 and Munc13-3). With the exception of a ubiquitously expressed Munc13-2 splice variant, Munc13 proteins are brain-specific. Munc13-1 has a central priming function in synaptic vesicle exocytosis from glutamatergic synapses. In order to identify Munc13-like proteins that may regulate secretory processes in non-glutamatergic neurons or non-neuronal cells, we developed protein profiles for two Munc13-homology-domains (MHDs). MHDs are present in a wide variety of proteins, some of which have previously been implicated in membrane trafficking reactions. Taking advantage of partial sequences in the human expressed sequence tag (EST) database, we characterized a novel, ubiquitously expressed, rat protein (Munc13-4) that belongs to a subfamily of Munc13-like molecules, in which the typical Munc13-like domain structure is conserved. Munc13-4 is predominantly expressed in lung where it is localized to goblet cells of the bronchial epithelium and to alveolar type II cells, both of which are cell types with secretory function. In the present study we identify a group of novel proteins, some of which may function in a Munc13-like manner to regulate membrane trafficking. The MHD profiles described in the present study are useful tools for the identification of Munc13-like proteins, that would otherwise have remained undetected.

Munc13-4, un nouvel effecteur indispensable à la sécrétion des granules cytotoxiques

“…La similitude d'architecture des domaines de Munc13-4 et de ceux des protéines de la famille Munc13/Unc13 explique que Munc13-4 a été inclus dans cette famille [10]. Les protéines Munc13 sont exclusivement ou très majoritairement exprimées dans le cerveau, et un rôle important de ces protéines dans la sécrétion du contenu des vésicules synaptiques neuronales a été postulé [11,12]…”

<b>Inhibitory role of Munc13-1 in antigen-induced mast cell </b><b>degranulation </b>

“…What is then the mechanism of the inhibition? Based on the conserved SNARE-binding region of the Munc13 family of proteins (18,20), Munc13-1 is likely to negatively regulate antigen-induced mast cell degranulation through its Ca 2+ -dependent SNARE-binding activity rather than through other unknown mechanism(s), which could involve the interference of the Munc13-4-mediated formation of trans-SNARE complexes. In other hematopoietic cells, Munc13-4 has been shown to function in the maturation and/or trafficking of late endosomes, in addition to its role in exocytosis (14,25).…”

“…The siRNA expression vector, pBAsi-mU6neo (Si-control), and the mammalian expression vector, pCIneo3HA (Vector), have been described previously (15,16). For the knockdown of rat Munc13-1, the target sequences 5′-GCGGC TGAGAAGAGTTCTA-3′ (KD1) and 5′-GCAAC AAGCCTGAGATCTT-3′ (KD2) were obtained using Invitrogen BLOCK-iT RNAi designer (http:// The Munc13 family comprises the following five proteins: Munc13-1, bMunc13-2, and Munc13-3, which were originally identified as neuronal isoforms, uMunc13-2, which was identified as a ubiquitously expressed splicing variant of bMunc13-2, and Munc13-4, which was identified as a non-neuronal isoform (20). Munc13-1, u/bMunc13-2, and Munc13-3 are involved in neurotransmitter release as expected (2,3,23,32); however, Munc13-1 is also required for insulin secretion in pancreatic β cells (21).…”

Genetic Markers of a Munc13 Protein Family Member, BAIAP3, Are Gender Specifically Associated with Anxiety and Benzodiazepine Abuse in Mice and Humans

“…To evaluate whether Baiap3 genotype would affect the propensity for di- D 1 9 : 1 3 5 -1 4 8 , 2 0 1 3 14.42 ± 3.70 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] 0.680 (Z = -0.41)…”

“…Baiap3 is a member of the mammalian uncoordinated 13 (Munc13) family of synaptic regulators of neurotransmitter exocytosis (23)(24)(25). Baiap3 has a unique and striking expression pattern (Allen Brain Atlas [http://mouse.brainmap.org]) in brain regions such as the central, medial and basomedial amygdaloid nuclei; the hypothalamus; and the periaqueductal gray.…”