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Comment
. 2018 Dec 18;115(51):12848-12850.
doi: 10.1073/pnas.1818608115. Epub 2018 Dec 11.

Getting a handle on CaV2.2 (N-type) voltage-gated Ca2+ channels

Jörg Striessnig  1
Affiliations
Comment

Getting a handle on CaV2.2 (N-type) voltage-gated Ca2+ channels

Jörg Striessnig. Proc Natl Acad Sci U S A. .
No abstract available

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Signaling pathways regulating CaV2.2 Ca2+ channel activity in peripheral somatosensory neurons and the role of α2δ-1 subunits. Presynaptic CaV2.2 (N-type) Ca2+ channels play a key role in neurotransmitter release in neurons, where they are positioned close to synaptic vesicles (8). This includes nerve terminals of primary somatosensory afferents (15). Their central pore-forming α-1 subunit requires associated accessory β and, as shown by Nieto-Rostro et al. (1) in vivo, α2δ subunits for proper function and trafficking to the plasma membrane (8). G protein-dependent inhibition contributes to opioid-induced analgesia (8) of CaV2.2 channels, and their direct block by intrathecal administration of the peptide toxin ziconotide (“Z”) produces analgesia in humans and in rodent pain models. GBPs (“G”) are approved for the treatment of some forms of neuropathic pain. In rodents, their analgesic actions require binding to α2δ-1 subunits (11). In vitro data suggest that this interferes with α2δ-1–dependent targeting of CaV2.2 channels to the plasma membrane—a hypothesis that can now be tested in vivo with the CaV2.2_HAKI/KI mouse model. Other mechanisms for indirectly inhibiting CaV2.2-channel signaling have been explored and have shown efficacy in rodent pain models. This includes peptides (blue) interfering with the cytoplasmic interaction of collapsin response mediator protein 2 (CRMP-2) with the channel (23) and a small molecule (compound 6, “6”) inhibiting β-3 subunit association (13). Meanwhile, other α2δ-1 binding proteins have been identified. An extracellular N-terminal domain of big potassium (BK) channels binds α2δ-1 subunits (black bar) and thereby may also sequester them away from (and thus inhibit) CaV2.2 channels. A BK channel N-terminus peptide negatively regulates CaV2.2 plasma membrane expression when expressed as a membrane-anchored construct (red) and its intrathecal delivery as viral construct has analgesic effects in rodents (24). Note that GBPs may also exert their analgesic actions via CaV2.2 channels in other brain areas, including central neurons of ascending or descending pain pathways (6). Moreover, GBPs can inhibit interactions between α2δ-1 and synaptogenic thrombospondin-4, which is also up-regulated in primary afferents after peripheral nerve damage and can induce aberrant excitatory synaptogenesis that may contribute to the development of chronic neuropathic pain (15). The α2δ-1 subunit also forms a complex with NMDA receptors (NMDA-Rs) in rodent and human spinal cords and promotes surface trafficking and synaptic targeting of NMDA-Rs upon nerve injury. This is inhibited by gabapentin or a peptide interfering with complex formation (20). The CaV2.2_HAKI/KI mice will be very useful for monitoring changes of CaV2.2 channel expression and plasma membrane targeting upon treatment with GBPs or novel mechanisms indirectly interfering with CaV2.2 trafficking and function.
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References

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