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.