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α2δ expression sets presynaptic calcium channel abundance and release probability.

Titleα2δ expression sets presynaptic calcium channel abundance and release probability.
Publication TypeJournal Article
Year of Publication2012
AuthorsHoppa MB, Lana B, Margas W, Dolphin AC, Ryan TA
Date Published2012 Jun 7
KeywordsAction Potentials, Animals, Calcium Channels, Calcium Signaling, Exocytosis, Mice, Neurotransmitter Agents, Presynaptic Terminals, Probability, Rats

Synaptic neurotransmitter release is driven by Ca(2+) influx through active zone voltage-gated calcium channels (VGCCs). 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 α1(A) VGCC subunit fails to change synaptic VGCC abundance or function. α2δs are a family of glycosylphosphatidylinositol (GPI)-anchored VGCC-associated subunits that, in addition to being the target of the potent neuropathic analgesics gabapentin and pregabalin (α2δ-1 and α2δ-2), were also identified in a forward genetic screen for pain genes (α2δ-3). We show that these proteins confer powerful modulation of presynaptic function through two distinct molecular mechanisms. First, α2δ subunits set synaptic VGCC abundance, as predicted from their chaperone-like function when expressed in non-neuronal cells. Second, α2δs 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 α2δ. Expression of α2δ with an intact MIDAS motif leads to an 80% increase in release probability, while simultaneously protecting exocytosis from blockade by an intracellular Ca(2+) chelator. α2δs harbouring MIDAS site mutations still drive synaptic accumulation of VGCCs; however, they no longer change release probability or sensitivity to intracellular Ca(2+) chelators. Our data reveal dual functionality of these clinically important VGCC subunits, allowing synapses to make more efficient use of Ca(2+) entry to drive neurotransmitter release.

Alternate JournalNature
PubMed ID22678293
PubMed Central IDPMC3376018
Grant ListR01 MH085783 / MH / NIMH NIH HHS / United States
R01 MH085783-01A1 / MH / NIMH NIH HHS / United States
R01 MH085783-02 / MH / NIMH NIH HHS / United States
R01 MH085783-03 / MH / NIMH NIH HHS / United States
R01 MH085783-04 / MH / NIMH NIH HHS / United States