Calcium-sensing receptor regulates Kv7 channels via Gi/o protein signalling and modulates excitability of human induced pluripotent stem cell-derived nociceptive-like neurons.

BACKGROUND AND PURPOSE: Neuropathic pain, a debilitating condition with unmet medical needs, can be characterised as hyperexcitability of nociceptive neurons caused by dysfunction of ion channels. Voltage-gated potassium channels type 7 (Kv7), responsible for maintaining neuronal resting membrane potential and thus excitability, reside under tight control of G protein-coupled receptors (GPCRs). Calcium-sensing receptor (CaSR) is a GPCR that regulates the activity of numerous ion channels, but whether CaSR can control Kv7 channel function has been unexplored until now. EXPERIMENTAL APPROACH: Experiments were conducted in recombinant cell models, mouse dorsal root ganglia (DRG) neurons and human induced pluripotent stem cell (hiPSC)-derived nociceptive-like neurons using patch-clamp electrophysiology and molecular biology techniques. KEY RESULTS: Our results demonstrate that CaSR is expressed in recombinant cell models, hiPSC-derived nociceptive-like neurons and mouse DRG neurons, and its activation induced depolarisation via Kv7.2/7.3 channel inhibition. The CaSR-Kv7.2/7.3 channel crosslink was mediated via the Gi/o protein-adenylate cyclase-cyclicAMP-protein kinase A signalling cascade. Suppression of CaSR function demonstrated a potential to rescue hiPSC-derived nociceptive-like neurons from algogenic cocktail-induced hyperexcitability. CONCLUSION AND IMPLICATIONS: This study demonstrates that the CaSR-Kv7.2/7.3 channel crosslink, via a Gi/o protein signalling pathway, effectively regulates neuronal excitability, providing a feasible pharmacological target for neuronal hyperexcitability management in neuropathic pain.

Suicide Rates in High-Risk High-Harm Perpetrators of Domestic Abuse in England and Wales.

Background A limited amount of research indicates a high prevalence of mental illness in perpetrators of domestic abuse (DA). Aims Estimate the suicide rate in high-risk high-harm perpetrators of DA. Method We utilized data collected as part of Drive, which supports and challenges perpetrators of DA to reduce their harmful behaviors. Using routine anonymized data, we established a cohort of clients (n = 3,475) who were referred via Multi-Agency Risk Assessment Conferences to the service and were followed up during service engagement. Results Most clients were male (92%) and White British (76%) with a median age of 32 years (IQI 27-39). There were 10 male suicide deaths recorded with an estimated male suicide rate of 461 per 100,000 person years (95% CI 248, 856). Limitations Analysis was restricted to those referred to the service and a specific group of perpetrators, limiting the generalizability to all perpetrators of DA. Conclusion The suicide rate in this high-risk high-harm DA perpetrator group is significantly higher than many other high-risk groups. Improving their mental health and outcomes is imperative to reduce the suicide deaths in this group and therefore reduce the impact such deaths would have on the victims of abuse.