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 Ca(V)1.2
calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of
hypertension. T-type (Ca(V)3) 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 (Ca(V)2.2)
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., Ca(V)1.2 and Ca(V)1.3 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 Ca(V)1.3 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.