In cochlea inner hair cells (IHCs), L-type Ca2؉ channels (LTCCs) formed by ␣1D subunits (D-LTCCs) possess biophysical and pharmacological properties distinct from those of ␣1C containing C-LTCCs. We investigated to which extent these differences are determined by ␣1D itself by analyzing the biophysical and pharmacological properties of cloned human ␣1D splice variants in tsA-201 cells. Variant ␣1D 8A, containing exon 8A sequence in repeat I, yielded ␣1D 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؉ ), ␣1D 8A -mediated currents activated at more negative voltages (activation threshold, ؊45.7 versus ؊31.5 mV, p < 0.05) and more rapidly ( act for maximal inward currents 0.8 versus 2.3 ms; p < 0.05) than currents mediated by rabbit ␣1C. Inactivation during depolarizing pulses was slower than for ␣1C (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 ␣1C. 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 ␣1D 8A subunits can form slowly inactivating LTCCs activating at more negative voltages than ␣1C. 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.L-type Ca 2ϩ channels (LTCCs) 1 form a family of voltagegated Ca 2ϩ channels with high sensitivity to dihydropyridine (DHP) Ca 2ϩ channel modulators. Their Ca 2ϩ -selective pore is formed by different DHP-sensitive ␣1 subunit isoforms (␣1S, ␣1C, ␣1D, ␣1F) together with auxiliary subunits, including ␣2-␦ and ␤ subunits (1-3). Whereas ␣1S and ␣1F expression is restricted to skeletal muscle and the retina, respectively, LTCCs formed by ␣1C (C-LTCCs) and ␣1D (D-LTCCs) subunits are widely expressed in neuronal and (neuro)endocrine cells as well as in electrically excitable cells in the cardiovascular system (4 -9). In most cases, both channel types are even found in the same cells, with D-LTCCs usually being the much less abundant isoform (7).Using D-LTCC-deficient mice, we have previously demonstrated that inward currents through ␣1D form LTCCs with biophysical and pharmacological properties distinct from CLTCCs (4, 6). These include a more negative range of current activation and slower current inactivation during depolarizations, allowing these channels to mediate long lasting Ca 2ϩ influx during weak depolarizations. Such properties allow LTCCs to control tonic neurotransmitter release in hair cells (5, 10), diastolic depolarization in the sinoatrial node (11), and electrical excitability of neurons (12-15).In addition to these different bi...

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USH1 molecules can assemble to a supramolecular complex at photoreceptor synapses. Such a complex may contribute to the cortical cytoskeletal matrices of the pre- and postsynaptic regions, which are thought to play a fundamental role in the organization of synaptic junctions. Dysfunction of any of the USH1 complex partners may lead to synaptic dysfunction causing retinitis pigmentosa, the clinical phenotype in the retina of patients with USH1. Furthermore, in photoreceptor outer segments, harmonin may also contribute to the clustering of outer segment proteins into supramolecular complexes.

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