Dystrobrevin Controls Neurotransmitter Release and Muscle Ca²⁺Transients by Localizing BK Channels inCaenorhabditis elegans

Abstract

Dystrobrevin is a major component of a dystrophin-associated protein complex (DAPC). It is widely expressed in mammalian tissues including the nervous system, where it is localized to the presynaptic nerve terminal with unknown function. In a genetic screen for suppressors of a lethargic phenotype caused by a gain-of-function (gf) isoform of SLO-1 in C. elegans, we isolated multiple loss-of-function (lf) mutants of the dystrobrevin gene dyb-1. dyb-1(lf) phenocopied slo-1(lf), causing increased neurotransmitter release at the neuromuscular junction, increased frequency of Ca2+ transients in body-wall muscle, and abnormal locomotion behavior. Neuron- and muscle-specific rescue experiments suggest that DYB-1 is required for SLO-1 function in both neurons and muscle cells. DYB-1 colocalized with SLO-1 at presynaptic sites in neurons and dense body regions in muscle cells, and dyb-1(lf) caused SLO-1 mislocalization in both types of cells without altering SLO-1 protein level. The neuronal phenotypes of dyb-1(lf) were partially rescued by mouse α-dystrobrevin-1 (αDB1). These observations revealed novel functions of the BK channel in regulating muscle Ca2+ transients, and of dystrobrevin in controlling neurotransmitter release and muscle Ca2+ transients by localizing the BK channel.

Role of CYP eicosanoids in the regulation of pharyngeal pumping and food uptake in Caenorhabditis elegans

“…Partially explaining the opposite effects, EETs activate whereas 20-HETE inhibits large conductance Ca 2+ -activated potassium (BK) channels in vascular smooth muscle cells ( 50,53 ). In C. elegans , BK channels are involved in regulating muscle Ca 2+ -transients ( 54,55 ) as well as neurotransmitter release at neuromuscular junction ( 56 ). 17,18-EEQ shares and, in several vascular beds, even largely exceeds the vasodilatory ( 57 ) and BK channel activating effects of EETs ( 58 ).…”

BK channel opening involves side-chain reorientation of multiple deep-pore residues

“…gating | structure-function | ion channel pore L arge-conductance, Ca 2+ -activated K + (BK) channels regulate physiological processes such as neurotransmitter release, smooth muscle contraction, and hair cell frequency tuning (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). BK channel proteins are homotetramers formed by BK α-subunits, which then associate with different β-or γ-subunits in a tissue-specific manner (13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Direct molecular interaction of caveolin-3 with KCa1.1 channel in living HEK293 cell expression system

“…[29]. It has been suggested that, in skeletal muscle from C. elegans, BK Ca channel expresses and functions stably by coupling with auxiliary subunits (BKIP [6], ISLO-1 [7]), a cytoskeletal protein (a-catulin [8,9]) and the dystrophin complex [11] and its components (DYS-1 [10], dystrobrevin [5]). In addition to forming the dystrophin complex, cav3 also functions as signal domains [30] and interacts with voltage-dependent Ca 2+ channel [31] and ryanodine receptor 1 (RyR1) [23,32], and contributes to excitation-contraction coupling (E-C coupling) [33].…”

“…In the previous study, we have shown the direct and functional interaction of BK Ca channel with cav1 to form functional molecular complex in living vascular smooth muscle cells and also in HEK293 expression system [19]. It remains, however, to be determined whether BK Ca channel directly interacts with cav3, whereas the possible functional interaction between BK Ca channel and dystrophin complex including cav3 in skeletal muscle has been suggested [5,11].…”

“…In mammalian skeletal muscle cells, BK Ca channels are localized at T-tubules and sarcolemma [3,4]. It has been found that, in Caenorhabditis elegans, BK Ca channel regulates Ca 2+ transients and maintains muscle excitability in body-wall muscle cells and controls neurotransmitter release in presynaptic nerve terminal [5]. Several auxiliary subunits of BK Ca channel [6,7], a cytoskeletal protein [8,9] and molecular complex with dystrophin [5,10,11], which provide a link between the cytoskeleton and the extracellular matrix, are required for proper BK Ca channel subcellular localization and functional activities in skeletal muscle.…”