pharmacological properties of Cav1.3. Strikingly, up to 8-fold differences in dihydropyridine sensitivity between alternatively spliced isoforms have been reported. Negative feedback Cav1.3 channels are regulated by negative feedback to achieve Ca2+ homeostasis. Calcium ions are a critical second messenger, intrinsic to intracellular signal transduction. Extracellular calcium levels are approximated to be 12000-fold greater than intracellular levels. During calcium-dependent processes, the intracellular level of calcium rises by up to 100-fold. It is vitally important to regulate this calcium gradient, not least because high levels of calcium are toxic to the cell, and can induce apoptosis. Ca2+-bound calmodulin (CaM) interacts with Cav1.3 to induce calcium-dependent inactivation (CDI). Recently, it has been shown that RNA editing of Cav1.3 transcripts is essential for CDI. Contrary to expectation, RNA editing does not simply attenuate the binding of CaM, but weakens the pre-binding of Ca2+-free calmodulin (apoCaM) to channels. The upshot is that CDI is continuously tuneable by changes in levels of CaM. Clinical significance Hearing Cav1.3 channels are widely expressed in humans. Notably, their expression predominates in cochlea inner hair cells (IHCs). Cav1.3 have been shown through patch clamp experiments to be essential for normal IHC development and synaptic transmission. Therefore, Cav1.3 are required for proper hearing. Chromaffin cells Cav1.3 are densely expressed in chromaffin cells. The low-voltage activation and slow inactivation of these channels makes them ideal for controlling excitability in these cells. Catecholamine secretion from chromaffin cells is particularly sensitive to L-type currents, associated with Cav1.3. Catecholamines have many systemic effects on multiple organs. In addition, L-type channels are responsible for exocytosis in these cells. Neurodegeneration Parkinson's disease is the second most common neurodegenerative disease, in which the death of dopamine-producing cells in the substantia nigra of the midbrain leads to impaired motor function, perhaps best characterised by tremor. Recent evidence suggests that L-type Cav1.3 Ca2+ channels contribute to the death of dopaminergic neurones in patients with Parkinson's disease. The basal activity of these neurones is also dependent on L-type Ca2+ channels, such as Cav1.3. Continuous pacemaking activity drives permanent intracellular dendritic and somatic calcium transients, which appears to make the dopaminergic substantia nigra neurones vulnerable to stressors that contribute to their death. Therefore inhibition of L-type channels, in particular Cav1.3 is protective against the pathogenesis of Parkinson's in some animal models. A clinical phase III trial (STEADY-PD III) testing this hypothesis in patients with early Parkinsons's failed to show efficacy in slowing