Abstract
Voltage-gated calcium channels (VGCCs) are widely expressed in the brain, heart and vessels, smooth and skeletal muscle, as well as in endocrine cells. VGCCs mediate gene transcription, synaptic and neuronal structural plasticity, muscle contraction, the release of hormones and neurotransmitters, and membrane excitability. Therefore, it is not surprising that VGCC dysfunction results in severe pathologies, such as cardiovascular conditions, neurological and psychiatric disorders, altered glycemic levels, and abnormal smooth muscle tone. The latest research findings and clinical evidence increasingly show the critical role played by VGCCs in autism spectrum disorders, Parkinson’s disease, drug addiction, pain, and epilepsy. These findings outline the importance of developing selective calcium channel inhibitors and modulators to treat such prevailing conditions of the central nervous system. Several small molecules inhibiting calcium channels are currently used in clinical practice to successfully treat pain and cardiovascular conditions. However, the limited palette of molecules available and the emerging extent of VGCC pathophysiology require the development of additional drugs targeting these channels. Here, we provide an overview of the role of calcium channels in neurological disorders and discuss possible strategies to generate novel therapeutics.
Highlights
Ion channels are the molecular underpinnings of membrane permeability and excitability and are essentially involved in the function of every organ in the body
Preclinical findings show that several small molecules that are in use for specific conditions of Voltage-gated calcium channels (VGCCs) may be potential candidates for additional applications
We report some compounds exhibiting isoform selectivity or the ability to offset aberrant signaling pathways downstream of calcium channel mutants that are associated with diseases
Summary
Ion channels are the molecular underpinnings of membrane permeability and excitability and are essentially involved in the function of every organ in the body. Small molecules directed at VGCCs available in medical practice include blockers, some of which lack the selectivity to channels’ isoforms and cause pronounced side effects. These inhibitors are not sufficient to treat VGCC-dependent diseases. New molecules targeting VGCCs need to be identified and characterized on channel-mediated functions In this manuscript, we discuss the impact of alternative splicing on channel drug sensitivity, the importance of restoring proper calcium current kinetics in dysfunctional channels, and the efficacy of selective blockers in the treatment of pain and seizure. Innovative molecules should selectively target only those channels involved in pathological processes, while sparing those participating in normal functions To this end, understanding the physio-pathological regulation of VGCCs and the underlying molecular and cellular mechanisms is paramount
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