alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages.

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Koschak A, Reimer D, Huber I, Grabner M, Glossmann H, Engel J, Striessnig J

alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages.

J Biol Chem. 2001 Jun 22;276(25):22100-6. Epub 2001 Apr 2.

PubMed ID

11285265 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Isradipine	Voltage-dependent L-type calcium channel subunit alpha-1D	Protein	Humans	Yes	Inhibitor	Details