Cav1.4α1 Subunits Can Form Slowly Inactivating Dihydropyridine-Sensitive L-Type Ca²⁺Channels Lacking Ca²⁺-Dependent Inactivation

The neuronal L-type calcium channels (LTCCs) Ca v 1.2α1 and Ca v 1.3α1 are functionally distinct. Ca v 1.3α1 activates at lower voltages and inactivates more slowly than Ca v 1.2α1, making it suitable to support sustained L-type Ca 2+ inward currents ( I Ca,L ) and serve in pacemaker functions. We compared the biophysical and pharmacological properties of human retinal Ca v 1.4α1 using the whole-cell patch-clamp technique after heterologous expression in tsA-201 cells with other L-type α1 subunits. Ca v 1.4α1-mediated inward Ba 2+ currents ( I Ba ) required the coexpression of α2δ1 and β3 or β2a subunits and were detected in a lower proportion of transfected cells than Ca v 1.3α1. I Ba activated at more negative voltages (5% activation threshold; -39mV; 15 m m Ba 2+ ) than Ca v 1.2α1 and slightly more positive than Ca v 1.3α1. Voltage-dependent inactivation of I Ba was slower than for Ca v 1.2α1 and Ca v 1.3α1(∼50% inactivation after 5 sec; α2δ1 + β3 coexpression). Inactivation was not increased with Ca 2+ as the charge carrier, indicating the absence of Ca 2+ -dependent inactivation. Ca v 1.4α1 exhibited voltage-dependent, G-protein-independent facilitation by strong depolarizing pulses. The dihydropyridine (DHP)-antagonist isradipine blocked Ca v 1.4α1 with ∼15-fold lower sensitivity than Ca v 1.2α1 and in a voltage-dependent manner. Strong stimulation by the DHP BayK 8644 was found despite the substitution of an otherwise L-type channel-specific tyrosine residue in position 1414 (repeat IVS6) by a phenylalanine. Ca v 1.4α1 + α2δ1 + β channel complexes can form LTCCs with intermediate DHP antagonist sensitivity lacking Ca 2+ -dependent inactivation. Their biophysical properties should enable them to contribute to sustained I Ca,L at negative potentials, such as required for tonic neurotransmitter release in sensory cells and plateau potentials in spiking neurons.