The varied sensitivities of the HVA and LVA channels to different antagonists show the potential for engineering these antagonists to selectively-alter the calcium conduction in different cells for various functions.
Their sequence similarity and evolutional relationship are shown in Figure 1. The following sections of the chapter will focus on comprehending the structure, and function of the LTCCs and their implications in drug discovery applications.
Phylogenetic tree showing the evolutionary relationship among the members of the VGCCs [ 2 , 17 ]. And, the major distribution of the four LTCC isoforms in human tissues [ 12 , 13 , 18 ]. The tree was constructed using the Clustal omega. Transcripts for all L-type channel isoforms have been detected in lymphocytes for endocrine functions [ 11 ]. In cardiomyocytes, CaV1.
When the LTCCs detect the electrical signal on the cell membrane, they transform these signals into other physiological activities, such as contraction of the muscle, secretion of hormones, and regulation of genes [ 18 , 19 ].
These processes can generally be summarized as excitation-contraction [ 18 ], excitation-secretion [ 19 ], and excitation-transcription coupling [ 12 ], respectively.
The other components serve as auxiliary subunits and modify the function of the channel. Figure 2 shows the arrangement of CaV subunits. The LTCC complex. All these channels have large numbers of potential splice variants expressed in different tissues [ 12 ]. The splicing sites are mainly distributed in the structurally flexible regions, such as N-terminal, C-terminal, and linkers between the transmembrane domains. They contribute to regulation of genes, gaining diversity in proteins, and in fine-tuning the physiological functions of the channel.
VSD detects the changes in the membrane potential and PD helps in the selective passage of calcium ions through the channel pore. The S4 helix of the VSD encompasses several conserved positively charged residues, whereas, the S1—S3 helices are dominated by negatively charged amino acids. When the membrane is depolarized, the movement of the S4 helices is transmitted to the cytoplasmic ends of the S5 and S6 helices, through the S4—S5 linkers, resulting in the opening of the activation gate formed by the S6 helices on the inner side of the channel [ 3 , 13 ].
The membrane-associated P-loop in each domain between the two helices, S5 and S6, form the selective filter of the channel. The selectivity of calcium channels relies on the P-loops domains and their calcium ion binding sites. The recent research identified three aspartic acid residues along the selectivity filter from extracellular to intracellular. Although the bacterial calcium channel is different from the mammalian LTCCs in their amino acid sequence and structural features, the structure of CavAb has provided valuable insights into calcium ion selectivity conferred by the selectivity filter.
The length of the C-terminus is much longer than N-terminus and contains several binding sites for various proteins that modulate the LTCCs activity shown in Figure 3.
When the DCRD is proteolytically cleaved, the cleaved fragment can remain non-covalently bound to the PCRD, thus allowing the two regions of the C-terminal domain to interact with each other and perform the auto-inhibitory function for the LTCCs [ 24 ].
The N-terminal domain is followed by four homologous transmembrane domains and the C-terminal domain. Each of the transmembrane domains is made of six helices and a membrane associated P-loop. The secondary structure is based on the PDBsum database. The high-affinity association between AID and ABP markedly influences the cell surface expression of functional channels [ 26 ].
This domain is known to have a possible role in small-molecule recognition [ 21 , 28 ]. Elucidating the three-dimensional 3D structure of membrane proteins is challenging due to their intricate environmental conditions. Until now, there are no complete 3D structures available for the human voltage-gated calcium channels. These structures have provided significant insights on the ion selectivity and drug-binding sites in the calcium channels.
The 2. The core region of rat CaV1. Chen et al. Their core structures, which includes the SH3 and GuK domains, exhibit high similarity. Mutation analysis showed that three CaV1.
In , a 2. Calmodulin CaM is a small and conserved calcium-binding messenger protein that plays an essential role in all the HVA channels. The IQ domain and the pre-IQ domain, upstream sequence of the IQ domain, serve as the binding site for the calmodulin.
In hippocampal neurons, CaV1. From to , several structures containing a short polypeptide from CaV1. In , three structures of the CaV1. In the CaV1. The lengths of CaV1. In , Fallon et al. Although CaV1. In , the first structure of a bacterial calcium channel CaVAb was resolved by performing specific mutations on the Arcobacter butzleri sodium channel NaVAb [ 5 ]. Four identical domains assemble to form the main structure of the channel, with each of the domain containing residues encompassing six transmembrane helices.
Tang et al. Each monomer is composed of a voltage-sensing domain S1—S4 and a pore-forming domain S5—S6. Four positively charged arginines in the voltage-sensing domain detect the changes in the membrane potential. The voltage-sensor movements are transmitted to the pore-forming domain through a cytoplasmic linker that connects the S4 and S5 helices.
A single substitution at site, from Glu to Asp, enhanced the calcium selectivity by times over sodium, which was sufficient to convert the sodium channel to calcium channel. Thus, the extracellular calcium ions fluently permeate into the intracellular side in response to the concentration gradient [ 5 ]. In , Wu et al. Following this complex, two rabbit CaV1. This CaV1.
While the 3D coordinates of most parts of the CaV1. The missing residues in the rabbit CaV1. The rabbit CaV1. Remarkably, the asymmetric pore-region of CaV1. Computational modeling and simulation remain to be a promising technique to reveal fundamental biological mechanisms, biomolecular interactions and predicting the effects of modulators. Neuropsychopharmacology 35 , — Rosse, R. Nimodipine pharmacotherapeutic adjuvant therapy for inpatient treatment of cocaine dependence.
Reimer, A. Nimodipine and haloperidol attenuate behavioural sensitization to cocaine but only nimodipine blocks the establishment of conditioned locomotion induced by cocaine.
Calcium-mediated second messengers modulate the expression of behavioral sensitization to cocaine. De Beun, R. Effects of nimodipine and other calcium channel antagonists in alcohol-preferring AA rats. Alcohol 13 , — Giordano, T. Molecular switch from L-type Cav1. This paper elegantly links L-type calcium channels to drug addiction. Schierberl, K. Channels 6 , 11—17 Rajadhyaksha, A. Liu, Y. Shulman, A. Calcium channel blocking drugs in the management of drug dependence, withdrawal and craving.
A clinical pilot study with nifedipine and verapamil. Physician 27 Suppl. Google Scholar. Jimenez-Lerma, J. Nimodipine in opiate detoxification: a controlled trial. Addiction 97 , — Newton, P. A blocker of N- and T-type voltage-gated calcium channels attenuates ethanol-induced intoxication, place preference, self-administration, and reinstatement.
This paper links the blockade of T-type and N-type channels to relief from alcohol addiction. Bhutada, P. Ferreira, M. This important study identifies Cav1. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet , — Wang, F. Bipolar Disord. Paulus, F. Brain Mapp. Erk, S. Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects.
Neuroimage 94 , — Ament, S. Rare variants in neuronal excitability genes influence risk for bipolar disorder. Gershon, E. Psychiatry 19 , — Yoshimizu, T. Psychiatry 20 , Ostacher, M. Pilot investigation of isradipine in the treatment of bipolar depression motivated by genome-wide association.
Splawski, I. Cell , 19—31 This manuscript reports on the devastating effects of a de novo mutation in Cav1. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. USA , —; discussion — Tian, Y. Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome.
Genome Med. Krey, J. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Pinggera, A. Psychiatry 77 , — Breitenkamp, A. Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function. Lu, A. Support for calcium channel gene defects in autism spectrum disorders. Autism 3 , 18 Duval, E.
Neural circuits in anxiety and stress disorders: a focused review. Risk Manag 11 , — Fox, A. Extending the amygdala in theories of threat processing. Trends Neurosci. Felix-Ortiz, A. Neuron 79 , — Ricord, M. Academy of Medicine: Paris. CAS Google Scholar. Nasca, C. Strawn, J. The treatment of generalized anxiety disorder with pregabalin, an atypical anxiolytic. Shinnick-Gallagher, P. L-type voltage-gated calcium channels are involved in the in vivo and in vitro expression of fear conditioning.
Lee, A. Forebrain elimination of cacna1c mediates anxiety-like behavior in mice. Psychiatry 17 , — Dao, D.
Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans. Psychiatry 68 , — Fulga, I. Experimental research on the effect of calcium channel blockers nifedipine and verapamil on the anxiety in mice. Busquet, P. Cassidy, J. Lee, J. T-type calcium channels and thalamocortical rhythms in sleep: a perspective from studies of T-type calcium channel knockout mice.
Drug Targets 6 , 63—69 Amer, A. Nasal administration of the calcium channel blocker diltiazem decreases food intake and attenuates weight gain in rats. Bell, T. Cell-specific alternative splicing increases calcium channel current density in the pain pathway.
Neuron 41 , — Differential role of N-type calcium channel splice isoforms in pain. This study follows up on findings in reference and shows that a unique Cav2. Chang, S. Neuroscience , — Michailidis, I. Neuron 82 , — Schrauwen, I. A mutation in CABP2 , expressed in cochlear hair cells, causes autosomal-recessive hearing impairment. Yang, P. Kuryshev, Y. Evaluating state dependence and subtype selectivity of calcium channel modulators in automated electrophysiology assays.
Brittain, J. Garcia-Caballero, A. The deubiquitinating enzyme USP5 modulates neuropathic and inflammatory pain by enhancing Cav3. Neuron 83 , — This study identifies deubiquitylation of Cav3. Small organic molecule disruptors of Cav3. Pain 11 , 12 Inagaki, A. Pharmacological correction of gating defects in the voltage-gated Cav2. Neuron 81 , 91— Fischer, T. A novel Nav1. The authors of this paper identify a sodium channel mutation in a patient with erythromelalgia, study the effect of the mutation in a recombinant expression system, and then use this information to design customized treatment of the patient.
Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Gerald W. Convergence Pharmaceuticals press release. A process by which an ion-channel-blocking drug becomes more effective during repetitive activation of the channel. Gabapentinoids are used as analgesics. A dihydropyridine that is used as an antihypertensive and currently being explored as a drug for Parkinson disease. Reprints and Permissions. Targeting voltage-gated calcium channels in neurological and psychiatric diseases.
Nat Rev Drug Discov 15, 19—34 Download citation. Published : 06 November Issue Date : January Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative. Molecular Brain Nature Communications Molecular Psychiatry Translational Psychiatry Advanced search. Skip to main content Thank you for visiting nature. Subjects Calcium channels Drug discovery Neurological disorders Psychiatric disorders. Key Points Voltage-gated calcium channels are of critical importance for nervous system function at the cellular and network levels.
Abstract Voltage-gated calcium channels are important regulators of brain, heart and muscle functions, and their dysfunction can give rise to pathophysiological conditions ranging from cardiovascular disorders to neurological and psychiatric conditions such as epilepsy, pain and autism.
Access through your institution. Buy or subscribe. Rent or Buy article Get time limited or full article access on ReadCube. Figure 1: Locations of drug interaction sites on voltage-gated calcium channels. Figure 2: Role of voltage-gated calcium channels in the primary afferent pain pathway. Figure 3: Role of T-type calcium channels in the thalamocortical circuitry. Figure 4: Role of L-type calcium channels in the degeneration of dopaminergic neurons during Parkinson disease.
Figure 5: Role of L-type calcium channels in drug addiction. References 1 Cain, S. Article Google Scholar 18 Catterall, W. Article Google Scholar 77 Jagodic, M. Article Google Scholar 84 Hendrich, J.
Article Google Scholar 88 Staats, P. Article Google Scholar 92 Feng, Z. Article Google Scholar Ziegler, D. Article Google Scholar Murakami, M. Article Google Scholar Blumenfeld, H. Article Google Scholar Guzman, J. Article Google Scholar Buttner, A. Article Google Scholar Rosse, R. Google Scholar Jimenez-Lerma, J. Article Google Scholar Newton, P. Article Google Scholar Erk, S. Article Google Scholar Download references. Acknowledgements G. Zamponi Authors Gerald W. Zamponi View author publications.
Ethics declarations Competing interests The author declares no competing financial interests. Related links. PowerPoint slides PowerPoint slide for Fig. PowerPoint slide for Fig. PowerPoint slide for Table 1. Glossary Calcium channels A group of membrane proteins that allow entry of calcium into cells. Alternative splicing A process by which one gene can create different variants of one protein. Parkinson disease A neurological disorder caused by a loss of dopaminergic neurons.
Epilepsy A neurological disorder in which patients present with seizures. Dihydropyridines A class of drug molecules that often act on calcium channels. Phenylalkylamines A specific class of small organic molecules that block calcium channels. Use-dependence A process by which an ion-channel-blocking drug becomes more effective during repetitive activation of the channel. Opioid A molecule that activates opioid receptors.
Gabapentin A compound that is used in the treatment of neuropathic pain. Pregabalin A compound that is used in the treatment of neuropathic pain. Neuropathic pain A chronic pain condition arising from a peripheral nerve injury. Z A blocker of N-type calcium channels that was explored as an analgesic.
Neuropathy A disease or dysfunction of peripheral nerves. Ethosuximide A type of anti-epileptic drug that acts on T-type calcium channels. Z A drug molecule that potently blocks T-type calcium channels. SNX A blocker of R-type calcium channels that is isolated from tarantula venom. Dorsal root ganglion DRG.
A cluster of nerve cell bodies comprising primary afferent sensory fibres. Polymorphisms The presence of genetic variations in a given population. Thalamus A specific brain region involved in functions such as sleep. The RYR channel is a protein of 45, amino acids expressed on the endoplasmic reticulum and sarcoplasmic reticulum with a relative molecular mass of , Calcium channel-related disease and the mechanism of the calcium channel working in these disease.
The study found that anti-depressants stimulate gynogenesis in hippocampus involving G-protein coupled receptors and voltage-dependent calcium channels. Clinical evidence suggests that L-type calcium channel blockers can treat bipolar disorder, schizophrenia, and a series of neuropsychiatric diseases such as depression. Cav1 and Cav3 molecules are associated with rodent emotions anxiety, depression , social behavior, and cognition.
Islet beta cells are very sensitive to changes in extracellular glucose concentration. When the extracellular glucose concentration is elevated, glucose is taken up into the beta cells through the glucose carrier on the beta cell membrane. A variety of drugs such as 2, 2-dithiodipyridine, thiopental, and interleukin 6 can induce or increase the effect of glucose-stimulated insulin secretion, all of which involve the release of calcium ions involved in the IP3R channel.
As the largest calcium reservoir in the cell, the endoplasmic reticulum has IP3R and RYR, which plays an important role in insulin secretion; in the rat insulinoma cell line INS1, insulin secretion can be inhibited by emptying the IP3-mediated calcium pool. All of the above experiments confirmed that the IP3R channel is involved in the insulin secretion process. This CICR process is glucose concentration dependent.
Phosphorylation of RYR2 is thought to be a mechanism that causes the release of intracellular calcium stores to mediate insulin secretion.
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