Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first‐in‐class synthetic version of ω‐conotoxin MVIIA, a peptide blocker of Cav2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use‐dependent block of Cav2.2 channels; activation state‐dependent blockers were hypothesized to circumvent the side effects of state‐independent blockers by selectively targeting high‐frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state‐dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans‐aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus‐evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant‐based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench‐to‐bedside translation of calcium channel modulators.Linked ArticlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc

The voltage-gated L-type Ca2+ channel CaV1.2 is crucial for initiating heartbeat and control of a number of neuronal functions such as neuronal excitability and long-term potentiation. Mutations of CaV1.2 subunits result in serious health problems including arrhythmia, autism spectrum disorders, immunodeficiency, and hypoglycemia. Thus precise control of CaV1.2 surface expression and localization is essential. We previously reported that α-actinin associates and colocalizes with neuronal CaV1.2 channels and that shRNA-mediated depletion of α-actinin significantly reduces localization of endogenous CaV1.2 in dendritic spines in hippocampal neurons. Here we investigated the hypothesis that direct binding of α-actinin to CaV1.2 supports its surface expression. Using two-hybrid screens and pull-down assays we identified three point mutations (K1647A, Y1649A, and I1654A) in the central, pore-forming α11.2 subunit of CaV1.2 that individually impaired α-actinin binding. Surface biotinylation and flow cytometry assays revealed that CaV1.2 channels composed of the corresponding α-actinin-binding-deficient mutants results in a 35–40% reduction in surface expression compared to wild-type channels. Moreover, the mutant CaV1.2 channels expressed in HEK293 cells exhibit a 60–75% reduction in current density. The larger decrease in current density as compared to surface expression imparted by these α11.2 subunit mutations hints at the possibility that α-actinin not only stabilizes surface localization of CaV1.2 but also augments its ion conducting activity.

The inhibitory effects of lidocaine and oxcarbazepine in this rat model of neuropathy resemble the clinical observations in the irritable nociceptor patient subgroup and support a mechanism-based rationale for bench-to-bedside translation when screening novel drugs.

Integrator 1 (BIN1), in the clustering of Ca v 1.2 channels in ventricular myocytes. Both of these proteins are known to directly interact with Ca v 1.2 channels. AKAP150 is important for local membrane targeting of PKA, PKCa and calcineurin, while Bin1 has established roles in cardiac t-tubule folding and in the trafficking and localization of Ca v 1.2 channels to t-tubules. Using GSD superresolution imaging, we found that clustering of Ca v 1.2 channels in these cells is unaltered by genetic ablation of AKAP79/150 such that the area of Ca V 1.2 clusters was similar in WT (2379 5 43 nm) and AKAP150 -/myocytes (2379 5 43 nm). However, heterozygous deletion of Bin1 significantly reduced Ca v 1.2 channel cluster size. The area of Ca V 1.2 channel clusters was approximately 42% smaller in BIN1 þ/-(1379 5 43 nm) than in WT (2349 5 76 nm 2 ) ventricular myocytes (p< 0.0001). This data suggests that Bin1 is a key regulator of Ca v 1.2 channel clustering in heart.