Our results, along with those obtained from the functional characterization of other CaV2.1 mutations linked to FHM (with or without severe cerebellar symptoms) and located at the distal part of α1A S6 α helices (i.e. V714A, D715E and I1881L, see S2 Fig) [60,63], entail a relevant role of the internal pore mouth in the control of CaV2.1 voltage-dependent gating, affecting both activation and inactivation of the channel. The gene discussed is CACNA1A; the disease is familial hemiplegic migraine.