Synaptic Vesicle Protein-2 (SV2)

Synaptic vesicle protein 2 (SV2) is an integral transmembrane glycoprotein expressed in all synaptic and endocrine vesicles. As a component of all vertebrate synaptic vesicles, SV2 has been proposed to function as a modulator of Ca²⁺-dependent neurotransmitter release in neurons.

Structure of SV2

SV2 consists of three isoforms, SV2A, SV2B and SV2C, with SV2A being the most widely expressed in the brain. All SV2 three isoforms contain 12 transmembrane (TM) domains with N- and C-terminal cytoplasmic sequences and a large intravesicular loop that is N-glycosylated. The TM domains and cytoplasmic loops are highly conserved in different SV2 isoforms, however, the intravesicular loop exhibits little homology although N-glycosylated in all SV2 isoforms. SV2 proteins exhibit a topology related to other transporter proteins, for example, the first six TM domains are homologous to the major facilitator superfamily (MFS), which is a member of human glucose transporters. Moreover, the other six TM domains of SV2 are closer to neurotransmitter transporters.

Table.1 SV2 protein family information summary. (Bartholome, 2017)

Function of SV2

• SV2A is the most studied isoform that is ubiquitously expressed in the brain including the cerebral cortex, hippocampus and cerebellum. It regulates the expression and trafficking of the synaptic vesicle calcium sensor protein, synaptotagmin, which is required for the calcium-mediated exocytosis of neurotransmitters. Besides, SV2A also plays a synaptotagmin-independent role in neurotransmitter release in a maturation step of primed synaptic vesicles.
• SV2B is widely expressed in the brain but undetectable in several groups of neurons in the hippocampus, central gray nuclei, and cerebellum. SV2B probably plays a role in the control of regulated secretion in neural and endocrine cells.
• SV2C has a much more restricted distribution being found mostly in the basal ganglia, midbrain, and brainstem. SV2C genetic deletion leads to a reduction in the synaptic release of dopamine, which is associated with a decrease in motor activity.

Fig.1 Interaction model of SV2A and Stonin 2 with Synaptotagmin 1. (Bartholome, 2017)

SV2 proteins, especially SV2A, are essential proteins and participate in the control of synaptic exocytosis. Abnormal neurotransmission was observed in SV2A knock-out (KO) mice. A recent study showed that a homozygous missense mutation (R383Q) in the SV2A gene resulted in intractable epilepsy, involuntary movements, microcephaly, and developmental retardation.

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Reference

1. Bartholome, O.; et al. Puzzling out synaptic vesicle 2 family members functions. Frontiers in molecular neuroscience. 2017, 10: 148.