In cochlea inner hair cells (IHCs), L-type Ca(2+) channels (LTCCs) formed by 
alpha1D subunits (D-LTCCs) possess biophysical and pharmacological properties 
distinct from those of alpha1C containing C-LTCCs. We investigated to which 
extent these differences are determined by alpha1D itself by analyzing the 
biophysical and pharmacological properties of cloned human alpha1D splice 
variants in tsA-201 cells. Variant alpha1D(8A,) containing exon 8A sequence in 
repeat I, yielded alpha1D protein and L-type currents, whereas no intact protein 
and currents were observed after expression with exon 8B. In whole cell 
patch-clamp recordings (charge carrier 15-20 mm Ba(2+)), alpha1D(8A) - mediated 
currents activated at more negative voltages (activation threshold, -45.7 versus 
-31.5 mV, p < 0.05) and more rapidly (tau(act) for maximal inward currents 0.8 
versus 2.3 ms; p < 0.05) than currents mediated by rabbit alpha1C. Inactivation 
during depolarizing pulses was slower than for alpha1C (current inactivation 
after 5-s depolarizations by 90 versus 99%, p < 0.05) but faster than for LTCCs 
in IHCs. The sensitivity for the dihydropyridine (DHP) L-type channel blocker 
isradipine was 8.5-fold lower than for alpha1C. Radioligand binding experiments 
revealed that this was not due to a lower affinity for the DHP binding pocket, 
suggesting that differences in the voltage-dependence of DHP block account for 
decreased sensitivity of D-LTCCs. Our experiments show that alpha1D(8A) subunits 
can form slowly inactivating LTCCs activating at more negative voltages than 
alpha1C. These properties should allow D-LTCCs to control physiological 
processes, such as diastolic depolarization in sinoatrial node cells, 
neurotransmitter release in IHCs and neuronal excitability.