Synaptic vesicle glycoprotein 2 (SV2)
Synaptic vesicle glycoprotein 2 (SV2) family and SV2-related protein (SVOP) are transporter-like proteins that are located in synaptic neurotransmitter-containing vesicles, but they do not transport neurotransmitters. The three SV2 genes in mammals encode three isoforms SV2A, SV2B, and SV2C. SV2A is ubiquitously and homogeneously located in presynaptic vesicle membranes across the brain, while SV2B and SV2C have more restricted distribution (Bajjalieh et al., 1994; Janz & Südhof, 1999; Bartholome et al., 2017). Each vesicle membrane contains ∼5 SV2 molecules, with little variation (Mutch et al., 2011). SVOP is distantly related to SV2 family proteins with 20-22% homology, and is present also in neuronal cell bodies, while SV2 proteins are only found in synapses. SVOP is evolutionarily conserved protein in vertebrates and invertebrates.
SV2 proteins and SVOP have structural similarities with the major facilitator (MF) family of small molecule transporters, including GLUTs. SV2 and SVOP are involved in the regulated secretion of neurotransmitters from presynaptic neurons (Nowack et al., 2010), possibly via synaptic vesicle recycling and calcium induced exocytosis. SV2 proteins bind synaptotagmin, which is a [Ca2+] sensor, and active during exocytosis (Rossi et al., 2022).
After vesicular fusion in exocytosis, SV2 proteins transiently become plasma membrane proteins. On plasma membrane, SV2 proteins can interact with components of extracellular matrix, especially laminin-1 (Rossi et al., 2022).
Botulinum an tetanus neurotoxins use certain synaptic proteins, including SV2 isoforms, as receptors for entry into neurons via the vesicle recycling mechanism (Baldwin & Barbieri, 2009; Rossi et al., 2022).
SV2 and SVOP bind nucleotides, such as ATP, GTP, and NAD, but with different affinities (Yao et al., 2009). SV2A may have a mitochondrial localization and function (Rossi et al., 2022).
SV2A (SLC22B1)
SV2A is present ubiquitously in the adult brain (including trigeminal nuclei and sphenopalatine ganglion) (Bartholome et al., 2017). Highest expression is in subcortical regions such as basal ganglia and thalamus (Rossi et al., 2022). SV2A expression level correlates well with classical markers of presynaptic terminals, such as synaptophysin and synaptotagmin. Therefore SV2A can be considered as a marker of synaptic density in the brain. SV2A expression can be high also outside brain, for example in endocrine pancreas.
SV2A is involved in the regulation of neurotransmitter release, but it can also transport galactose (Madeo et al., 2014).
SV2A is the binding site of racetam family of epilepsy drugs, including brivaracetam and levetiracetam. SV2A modulates epileptogenesis via GABAergic, but not glutamatergic system (Ohno & Tokudome, 2017).
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Levetiracetam has been labelled with 11C (Cai et al., 2014), and based on its structure, several other PET radioligands with higher affinity for SV2A have been developed (Warnock et al., 2014; Estrada et al., 2016; Nabulsi et al., 2016; Li et al., 2019; Patel et al., 2020; Cai et al., 2020; Zheng et al., 2022).
[11C]UCB-J binds specifically to SV2A, and has favourable kinetics to be used to assess the synaptic density in vivo in humans (Nabulsi et al., 2016; Finnema et al., 2016). [18F]SynVesT-1 ([18F]MNI-1126, (R)-[18F]SDM-8) may have faster kinetics than [11C]UCB-J (Cai et al., 2018; Li et al., 2018, 2019, and 2021; Naganawa et al., 2021). [18F]SynVesT-1 has shown similar brain distribution as [11C]UCB-J, and higher BPND when centrum semiovale (white matter underneath the cerebral cortex) was used as reference region (Constantinescu et al., 2019; Naganawa et al., 2021). Brain stem and cerebellum have been used as reference region in mice studies with [18F]SynVesT-1 (Sadasivam et al., 2021); however, a blocking study in mice with [18F]SynVesT-1 has shown that no reference region exists (Bertoglio et al., 2022). Both [11C]UCB-J and [18F]SynVesT-1 have excellent test-retest reproducibility (Li et al., 2021). Scan durations of 30-120 min with [18F]SynVesT-1 provide similar test-retest reproducibility (Li et al., 2021). Even in mice, VT results from 60 min scan provide good reproducibility (Bertoglio et al., 2022). [18F]UCB-H has been found to be specific for SV2A against SV2B and SV2C in rats (Serrano et al., 2019), and SUV from static 20-40 min scan correlated well with VT (Serrano et al., 2020). The specific binding of [18F]UCB-H is relatively low, hampering quantification (Goutal et al., 2021).
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[11C]UCB-A and [18F]SDM-16 are metabolically more stable than most SV2A radioligands (Zheng et al., 2022).
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Reductions in SV2A binding have been seen around the epileptic focus in temporal lobe epilepsy patients, in the cortical areas of patients with mood disorders, PTSD, schizophrenia, Alzheimer's disease, and ALS (Rabiner, 2018; Holmes et al., 2019; Onwordi et al., 2020; Tang et al., 2022). Synaptic loss has been seen in brainstem nuclei in Parkinson's disease (Matuskey et al., 2020). In Huntington's disease, reduced SV2A binding is seen in putamen, caudate, pallidum, cerebellum, and parietal, temporal, and frontal cortices (Delva et al., 2021).
[11C]UCB-J has been used to assess SV2A occupancy of anti-epileptic drugs (Rabiner, 2018; Finnema et al., 2019).
SV2A is expressed not only in the brain, but also in neuroendocrine cells and at neuromuscular junctions (Bartholome et al., 2017). SV2A could serve as a target for PET imaging in neuroendocrine prostate cancer (Guan et al., 2021).
SV2B (SLC22B2)
SV2B expression is high in the cortex and hippocampus, but it is absent in the globus pallidus, hippocampal dentate gyrus, reticular substantia nigra, and reticular thalamic nucleus (Bartholome et al., 2017; Hu et al., 2017; Rossi et al., 2022). Expression of SV2B seems to be restricted to some glutamatergic neurons.
SV2B expression is downregulated in Alzheimer's disease (Bartholome et al., 2017).
SV2C (SLC22B3)
In humans, SV2C is expressed in evolutionarily old brain regions, including striatum, substantia nigra nuclei in the pons and medulla oblongata. Low levels are found in olfactory bulb, cerebrum, cerebellum, and hippocampus (Bartholome et al., 2017; Rossi et al., 2022). SV2C is expressed in dopaminergic neurons, certain GABAergic neurons, such as Purkinje cells of the cerebellum, and in some cholinergic neurons (Bartholome et al., 2017; Rossi et al., 2022). SV2C regulates dopamine release (Dunn et al., 2017), and is involved in hypertension, venous thromboembolism and coagulation pathways (Janz & Südhof, 1999; Hu et al., 2017).
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Literature
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Tags: Synaptic density, SV2A
Updated at: 2023-02-05
Created at: 2017-11-28
Written by: Vesa Oikonen