Synaptic vesicle glycoprotein 2A modulates vesicular release and calcium channel function at peripheral sympathetic synapses

Abstract

Synaptic vesicle glycoprotein (SV)2A is a transmembrane protein found in secretory vesicles and is critical for Ca(2+) -dependent exocytosis in central neurons, although its mechanism of action remains uncertain. Previous studies have proposed, variously, a role of SV2 in the maintenance and formation of the readily releasable pool (RRP) or in the regulation of Ca(2+) responsiveness of primed vesicles. Such previous studies have typically used genetic approaches to ablate SV2 levels; here, we used a strategy involving small interference RNA (siRNA) injection to knockdown solely presynaptic SV2A levels in rat superior cervical ganglion (SCG) neuron synapses. Moreover, we investigated the effects of SV2A knockdown on voltage-dependent Ca(2+) channel (VDCC) function in SCG neurons. Thus, we extended the studies of SV2A mechanisms by investigating the effects on vesicular transmitter release and VDCC function in peripheral sympathetic neurons. We first demonstrated an siRNA-mediated SV2A knockdown. We showed that this SV2A knockdown markedly affected presynaptic function, causing an attenuated RRP size, increased paired-pulse depression and delayed RRP recovery after stimulus-dependent depletion. We further demonstrated that the SV2A-siRNA-mediated effects on vesicular release were accompanied by a reduction in VDCC current density in isolated SCG neurons. Together, our data showed that SV2A is required for correct transmitter release at sympathetic neurons. Mechanistically, we demonstrated that presynaptic SV2A: (i) acted to direct normal synaptic transmission by maintaining RRP size, (ii) had a facilitatory role in recovery from synaptic depression, and that (iii) SV2A deficits were associated with aberrant Ca(2+) current density, which may contribute to the secretory phenotype in sympathetic peripheral neurons.

Imaging biomarkers in neurodegeneration: current and future practices

“…SV2A is the most ubiquitous and is expressed as a transmembrane glycoprotein in secretory vesicles on presynaptic terminals. It is critical to synaptic function, particularly Ca2+-dependent exocytosis [86], and is known to be the binding site of levetiracetam [87].…”

Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug‐Naive Parkinson's Disease

“…(3) naive to PD treatment at baseline; (4) did not fulfill the diagnostic criteria for PD mild cognitive impairment, 33 dementia, 34 or depression 35 ); (5) no history of other neurological or psychiatric disorders; and (6) no contraindication to MRI. Healthy controls had no history of neurological or psychiatric disorders.…”

“…Synaptic vesicle protein 2A (SV2A) is a transmembrane protein widely expressed in presynaptic terminals throughout the brain, where it regulates neurotransmission. 4,5 Neurons lacking SV2A demonstrate impaired ability of vesicles to fuse with the plasma membrane. 6 There are several lines of evidence suggesting that accumulation of α-synuclein in presynaptic terminals impairs synaptic proteins, synaptic plasticity, and neurotransmission and subsequently induces axonal damage and impairment of intracellular trafficking.…”

Epilepsy, Antiepileptic Drugs, and Aggression: An Evidence-Based Review

“…Levetiracetam has a clear and distinct mechanism of action; it acts on the SV2A integral membrane glycoprotein present on all synaptic vesicles ( Lynch et al, 2004 ). Recent work by Vogl et al (2015) in superior cervical ganglion neurons demonstrated that SV2A maintained normal neurotransmission by regulating readily releasable pool size, had a facilitatory role in recovery from synaptic depression, and impaired presynaptic voltage-dependent Ca 2+ channel current density. Specific details on the mechanisms of action of AEDs at the level of receptors and ion channels have been extensively reviewed ( Kwan et al, 2001 ; Löscher et al, 2013 ; Moshé et al, 2015 ).…”