T-type calcium channels perform crucial physiological roles across a wide spectrum of tissues, spanning both neuronal and non-neuronal system. For instance, they serve as pivotal regulators of neuronal excitability, contribute to cardiac pacemaking, and mediate the secretion of hormones. These functions significantly hinge upon the intricate interplay of T-type channels with interacting proteins that modulate their expression and function at the plasma membrane. In this review, we offer a panoramic exploration of the current knowledge surrounding these T-type channel interactors, and spotlight certain aspects of their potential for drug-based therapeutic intervention.

• Keywords
• Calcium channels, Channelosome, Ion channels, T-type channels,
• MeSH
• Calcium Channel Blockers MeSH
• Neurons metabolism   MeSH
• Calcium * metabolism   MeSH
• Calcium Channels, T-Type * metabolism   MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Calcium Channel Blockers MeSH
• Calcium * MeSH
• Calcium Channels, T-Type * MeSH

T-type calcium channelopathies encompass a group of human disorders either caused or exacerbated by mutations in the genes encoding different T-type calcium channels. Recently, a new heterozygous missense mutation in the CACNA1H gene that encodes the Cav3.2 T-type calcium channel was reported in a patient presenting with epilepsy and hearing loss-apparently the first CACNA1H mutation to be associated with a sensorineural hearing condition. This mutation leads to the substitution of an arginine at position 132 with a histidine (R132H) in the proximal extracellular end of the second transmembrane helix of Cav3.2. In this study, we report the electrophysiological characterization of this new variant using whole-cell patch clamp recordings in tsA-201 cells. Our data reveal minor gating alterations of the channel evidenced by a mild increase of the T-type current density and slower recovery from inactivation, as well as an enhanced sensitivity of the channel to external pH change. To what extend these biophysical changes and pH sensitivity alterations induced by the R132H mutation contribute to the observed pathogenicity remains an open question that will necessitate the analysis of additional CACNA1H variants associated with the same pathologies.

• Keywords
• CACNA1H, Calcium channels, Cav3.2, Channelopathy, Epilepsy, Hearing, Ion channels, Mutation, T-type channels,
• MeSH
• Epilepsy * genetics   MeSH
• Humans MeSH
• Mutation, Missense genetics   MeSH
• Mutation genetics   MeSH
• Hearing Loss * MeSH
• Calcium Channels MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Calcium Channels MeSH

Trigeminal neuralgia (TN) is a rare form of chronic neuropathic pain characterized by spontaneous or elicited paroxysms of electric shock-like or stabbing pain in a region of the face. While most cases occur in a sporadic manner and are accompanied by intracranial vascular compression of the trigeminal nerve root, alteration of ion channels has emerged as a potential exacerbating factor. Recently, whole exome sequencing analysis of familial TN patients identified 19 rare variants in the gene CACNA1H encoding for Cav3.2T-type calcium channels. An initial analysis of 4 of these variants pointed to a pathogenic role. In this study, we assessed the electrophysiological properties of 13 additional TN-associated Cav3.2 variants expressed in tsA-201 cells. Our data indicate that 6 out of the 13 variants analyzed display alteration of their gating properties as evidenced by a hyperpolarizing shift of their voltage dependence of activation and/or inactivation resulting in an enhanced window current supported by Cav3.2 channels. An additional variant enhanced the recovery from inactivation. Simulation of neuronal electrical membrane potential using a computational model of reticular thalamic neuron suggests that TN-associated Cav3.2 variants could enhance neuronal excitability. Altogether, the present study adds to the notion that ion channel polymorphisms could contribute to the etiology of some cases of TN and further support a role for Cav3.2 channels.

• Keywords
• CACNA1H, Calcium channel, Cav3.2 channel, Channelopathy, Ion channel, Trigeminal neuralgia,
• MeSH
• Electrophysiological Phenomena MeSH
• Humans MeSH
• Membrane Potentials MeSH
• Trigeminal Neuralgia * genetics   MeSH
• Neurons MeSH
• Calcium Channels MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CACNA1H protein, human MeSH Browser
• Calcium Channels MeSH

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873-4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

• Keywords
• CACNA1H, Calcium channel, Cav3.2 channel, Channelopathy, Encephalopathy, Epilepsy, Ion channels, Nav1.6 channel, SCN8A, Sodium channel,
• MeSH
• Gain of Function Mutation MeSH
• Point Mutation MeSH
• Gene Duplication MeSH
• Epilepsy, Tonic-Clonic genetics   MeSH
• Ion Channel Gating genetics   physiology   MeSH
• Genetic Predisposition to Disease MeSH
• Humans MeSH
• Mutation, Missense MeSH
• Abnormalities, Multiple genetics   MeSH
• NAV1.6 Voltage-Gated Sodium Channel genetics   physiology   MeSH
• Infant, Newborn MeSH
• Drug Resistant Epilepsy genetics   MeSH
• Pedigree MeSH
• Scoliosis genetics   MeSH
• Calcium Channels, T-Type genetics   physiology   MeSH
• Developmental Disabilities genetics   MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• CACNA1H protein, human MeSH Browser
• NAV1.6 Voltage-Gated Sodium Channel MeSH
• SCN8A protein, human MeSH Browser
• Calcium Channels, T-Type MeSH

Cav3.2 T-type calcium channels play an essential role in the transmission of peripheral nociception in the dorsal root ganglia (DRG) and alteration of Cav3.2 expression is associated with the development of peripheral painful diabetic neuropathy (PDN). Several studies have previously documented the role of glycosylation in the expression and functioning of Cav3.2 and suggested that altered glycosylation of the channel may contribute to the aberrant expression of the channel in diabetic conditions. In this study, we aimed to analyze the expression of glycan-processing genes in DRG neurons from a leptin-deficient genetic mouse model of diabetes (db/db). Transcriptomic analysis revealed that several glycan-processing genes encoding for glycosyltransferases and sialic acid-modifying enzymes were upregulated in diabetic conditions. Functional analysis of these enzymes on recombinant Cav3.2 revealed an unexpected loss-of-function of the channel. Collectively, our data indicate that diabetes is associated with an alteration of the glycosylation machinery in DRG neurons. However, individual action of these enzymes when tested on recombinant Cav3.2 cannot explain the observed upregulation of T-type channels under diabetic conditions.Abbreviations: Galnt16: Polypeptide N-acetylgalactosaminyltransferase 16; B3gnt8: UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 8; B4galt1: Beta-1,4-galactosyltransferase 1; St6gal1: Beta-galactoside alpha-2,6-sialyltransferase 1; Neu3: Sialidase-3.

• Keywords
• Cav3.2 channel, DRG neurons, Glycosylation, T-type channel, calcium channel, diabetes, transcriptome,
• MeSH
• Cell Line MeSH
• Electrophysiology methods   MeSH
• Diabetes Mellitus, Experimental metabolism   MeSH
• Glycosylation MeSH
• Humans MeSH
• Mice MeSH
• Polysaccharides metabolism   MeSH
• Ganglia, Spinal metabolism   MeSH
• Transcriptome genetics   MeSH
• Calcium Channels, T-Type genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cacna1h protein, mouse MeSH Browser
• Polysaccharides MeSH
• Calcium Channels, T-Type MeSH

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACNA1H encoding for Cav3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Cav3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominant-negative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Cav3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Cav3.2 channel function. These findings add to the notion that loss-of-function of Cav3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.

• Keywords
• ALS, Amyotrophic lateral sclerosis, Biophysics, CACNA1H, Calcium channel, Cav3.2 channel, Motor neuron disease, Mutation, T-type channel,
• MeSH
• Amyotrophic Lateral Sclerosis * genetics   MeSH
• Genes, Dominant MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Association Studies * MeSH
• Heterozygote MeSH
• Rats MeSH
• Humans MeSH
• Mutation * genetics   MeSH
• Amino Acid Sequence MeSH
• Whole Genome Sequencing MeSH
• Structural Homology, Protein MeSH
• Calcium Channels, T-Type * chemistry   genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CACNA1H protein, human MeSH Browser
• Calcium Channels, T-Type * MeSH

T-type channels are low-voltage-activated calcium channels that contribute to a variety of cellular and physiological functions, including neuronal excitability, hormone and neurotransmitter release as well as developmental aspects. Several human conditions including epilepsy, autism spectrum disorders, schizophrenia, motor neuron disorders and aldosteronism have been traced to variations in genes encoding T-type channels. In this short review, we present the genetics of T-type channels with an emphasis on structure-function relationships and associated channelopathies.

• Keywords
• aldosteronism, amyotrophic lateral sclerosis, autism spectrum disorders, calcium channels, cav3 channels, channelopathies, epilepsy, mutation, schizophrenia, t-type channels,
• MeSH
• Channelopathies genetics   metabolism   MeSH
• Humans MeSH
• Mutation MeSH
• Calcium Channels genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Calcium Channels MeSH