alpha 2 delta expression sets presynaptic calcium channel abundance and release probability

Article

关键词: GATED CA2+ CHANNELS;    FACTOR-A DOMAIN;    SYNAPTIC-TRANSMISSION;    NEUROTRANSMITTER RELEASE;    ALPHA(2)DELTA SUBUNITS;    FUNCTIONAL-PROPERTIES;    FLUORESCENT PROTEINS;    PLASMA-MEMBRANE;    TRAFFICKING;    CA(V)2.1;   

DOI  :  10.1038/nature11033

来源: SCIE

【 摘 要 】

Synaptic neurotransmitter release is driven by Ca2+ influx through active zone voltage-gated calcium channels (VGCCs)(1,2). Control of active zone VGCC abundance and function remains poorly understood. Here we show that a trafficking step probably sets synaptic VGCC levels in rats, because overexpression of the pore-forming alpha 1(A) VGCC subunit fails to change synaptic VGCC abundance or function. alpha 2 delta s are a family of glycosylphosphatidylinositol (GPI)-anchored VGCC-associated subunits(3) that, in addition to being the target of the potent neuropathic analgesics gabapentin and pregabalin (alpha 2 delta-1 and alpha 2 delta-2)(4,5), were also identified in a forward genetic screen for pain genes (alpha 2 delta-3)(6). We show that these proteins confer powerful modulation of presynaptic function through two distinct molecular mechanisms. First, alpha 2 delta subunits set synaptic VGCC abundance, as predicted from their chaperone-like function when expressed in non-neuronal cells(3,7). Second, alpha 2 delta s configure synaptic VGCCs to drive exocytosis through an extracellular metal ion-dependent adhesion site (MIDAS), a conserved set of amino acids within the predicted von Willebrand A domain of alpha 2 delta. Expression of alpha 2 delta with an intact MIDAS motif leads to an 80% increase in release probability, while simultaneously protecting exocytosis from blockade by an intracellular Ca2+ chelator. alpha 2 delta s harbouring MIDAS site mutations still drive synaptic accumulation of VGCCs; however, they no longer change release probability or sensitivity to intracellular Ca2+ chelators. Our data reveal dual functionality of these clinically important VGCC subunits, allowing synapses to make more efficient use of Ca2+ entry to drive neurotransmitter release.

【 授权许可】

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