The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential
Top Cited Papers
Open Access
- 2 September 2015
- journal article
- review article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Pharmacological Reviews
- Vol. 67 (4), 821-870
- https://doi.org/10.1124/pr.114.009654
Abstract
Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described and their physiologic roles and pharmacology are outlined. We describe the current uses of drugs interacting with the different calcium channel subtypes and subunits, as well as specific areas in which there is strong potential for future drug development. Current therapeutic agents include drugs targeting L-type CaV1.2 calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (CaV3) channels are a target of ethosuximide, widely used in absence epilepsy. The auxiliary subunit α2δ-1 is the therapeutic target of the gabapentinoid drugs, which are of value in certain epilepsies and chronic neuropathic pain. The limited use of intrathecal ziconotide, a peptide blocker of N-type (CaV2.2) calcium channels, as a treatment of intractable pain, gives an indication that these channels represent excellent drug targets for various pain conditions. We describe how selectivity for different subtypes of calcium channels (e.g., CaV1.2 and CaV1.3 L-type channels) may be achieved in the future by exploiting differences between channel isoforms in terms of sequence and biophysical properties, variation in splicing in different target tissues, and differences in the properties of the target tissues themselves in terms of membrane potential or firing frequency. Thus, use-dependent blockers of the different isoforms could selectively block calcium channels in particular pathologies, such as nociceptive neurons in pain states or in epileptic brain circuits. Of important future potential are selective CaV1.3 blockers for neuropsychiatric diseases, neuroprotection in Parkinson’s disease, and resistant hypertension. In addition, selective or nonselective T-type channel blockers are considered potential therapeutic targets in epilepsy, pain, obesity, sleep, and anxiety. Use-dependent N-type calcium channel blockers are likely to be of therapeutic use in chronic pain conditions. Thus, more selective calcium channel blockers hold promise for therapeutic intervention.Keywords
This publication has 184 references indexed in Scilit:
- What can naturally occurring mutations tell us about Cav1.x channel function?Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013
- Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: Expanding the spectrum of Timothy syndromeAmerican Journal of Medical Genetics Part A, 2011
- Mood Disorder Susceptibility Gene CACNA1C Modifies Mood-Related Behaviors in Mice and Interacts with Sex to Influence Behavior in Mice and Diagnosis in HumansBiological Psychiatry, 2010
- L‐type calcium channel blockers and Parkinson disease in DenmarkAnnals of Neurology, 2010
- Rebound Discharge in Deep Cerebellar Nuclear Neurons In VitroThe Cerebellum, 2010
- Do Calcium Channel Blockers Rescue Dying Photoreceptors in the Pde6b rd1 Mouse?Advances in experimental medicine and biology, 2009
- Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS SynaptogenesisCell, 2009
- A CaV1.1 Ca2+ Channel Splice Variant with High Conductance and Voltage-Sensitivity Alters EC Coupling in Developing Skeletal MuscleBiophysical Journal, 2009
- Ca2+ signal summation and NFATc1 nuclear translocation in sympathetic ganglion neurons during repetitive action potentialsCell Calcium, 2007
- Amiloride and its analogs as tools in the study of ion transportThe Journal of Membrane Biology, 1988