Fig. 1
Electrophysiological properties of the Cav1.2 L658P variant. A Location of the L658P missense variant (red dot) within the secondary membrane topology of Cav1.2 channel. B Amino acid sequence alignment of the IIS5 transmembrane segment showing the conservation of the L658 residue across the 10 human voltage-gated calcium channel isoforms. Alignments were performed using UniProt (Cav1.1 Q13698; Cav1.2 Q13936; Cav1.3 Q01668; Cav1.4 O60840; Cav2.1 O00555; Cav2.2 Q00975; Cav2.3 Q15878; Cav3.1 O43497; Cav3.2 O95180; Cav3.3 Q9P0X4). C Representative L-type current traces recorded from tsA-201 cells expressing Cav1.2 wild-type (WT, black traces) and L658P variant channels (red traces), in combination with Cavβ2, and Cavα2δ1. D Corresponding mean current–voltage (I/V) relationship. E Mean maximal macroscopic conductance (Gmax) obtained from the fit of the I/V curves with the modified Boltzmann Eq. (1). F Mean reversal potential (Vrev) values. G Mean normalized voltage dependence of activation. H Mean half-activation potential (V0.5 activation) values obtained from the fit of the activation curves with the modified Boltzmann Eq. (2). I Mean normalized voltage dependence of steady state inactivation. J Mean half-inactivation potential (V0.5 inactivation) values obtained from the fit of the inactivation curves with the modified Boltzmann Eq. (3). K Mean non-inactivating channel fraction values. L Mean window currents calculated from the activation and inactivation curves using the Eq. (4). The squared area shows the window current between − 70 and − 55 mV, corresponding to a range of neuronal resting membrane potentials. M Mean window current values calculated from the area under the curve between − 70 and − 55 mV. N Mean time constant τ values of current activation kinetics. O Mean time constant τ values of current inactivation kinetics. P Mean normalized recovery of inactivation kinetics. Q Mean time constant τ values of recovery from inactivation obtained by fitting the recovery curves with a single-exponential Eq. (5). R Dose–response of Cav1.2 channels for isradipine. S Dose–response of Cav1.2 channels for verapamil. T Molecular modeling of Cav1.2 showing the impact of the L658P mutation on various superimposed Cav1.2 channel states including resting (cyan), near-open (green), and high-voltage inactivated states (yellow and orange)