Cav1.3‐selective inhibitors of voltage‐gated L‐type Ca2+ channels: Fact or (still) fiction?

Abstract

Voltage‐gated L‐type Ca2+‐channels (LTCCs) are the target of Ca2+‐channel blockers (CCBs), which are in clinical use for the evidence‐based treatment of hypertension and angina. Their cardiovascular effects are largely mediated by the Cav1.2‐subtype. However, based on our current understanding of their physiological and pathophysiological roles, Cav1.3 LTCCs also appear as attractive drug targets for the therapy of various diseases, including treatment‐resistant hypertension, spasticity after spinal cord injury and neuroprotection in Parkinson's disease. Since CCBs inhibit both Cav1.2 and Cav1.3, Cav1.3‐selective inhibitors would be valuable tools to validate the therapeutic potential of Cav1.3 channel inhibition in preclinical models. Despite a number of publications reporting the discovery of Cav1.3‐selective blockers, their selectivity remains controversial. We conclude that at present no pharmacological tools exist that are suitable to confirm or refute a role of Cav1.3 channels in cellular responses. We also suggest essential criteria for a small molecule to be considered Cav1.3‐selective.