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

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

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

Low-voltage-activated T-type calcium channels are essential contributors to the functioning of thalamocortical neurons by supporting burst-firing mode of action potentials. Enhanced T-type calcium conductance has been reported in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and proposed to be causally related to the overall development of absence seizure activity. Here, we show that calnexin, an endoplasmic reticulum integral membrane protein, interacts with the III-IV linker region of the Cav3.2 channel to modulate the sorting of the channel to the cell surface. We demonstrate that the GAERS missense mutation located in the Cav3.2 III-IV linker alters the Cav3.2/calnexin interaction, resulting in an increased surface expression of the channel and a concomitant elevation in calcium influx. Our study reveals a novel mechanism that controls the expression of T-type channels, and provides a molecular explanation for the enhancement of T-type calcium conductance in GAERS.

• MeSH
• Epilepsy, Absence genetics   MeSH
• Calnexin metabolism   MeSH
• Rats MeSH
• Mutation, Missense * MeSH
• Disease Models, Animal MeSH
• Mutant Proteins genetics   metabolism   MeSH
• Protein Transport MeSH
• Calcium Channels, T-Type genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cacna1h protein, rat MeSH Browser
• Calnexin MeSH
• Mutant Proteins MeSH
• Calcium Channels, T-Type MeSH

Neuronal voltage-gated calcium channels (VGCCs) serve complex yet essential physiological functions via their pivotal role in translating electrical signals into intracellular calcium elevations and associated downstream signalling pathways. There are a number of regulatory mechanisms to ensure a dynamic control of the number of channels embedded in the plasma membrane, whereas alteration of the surface expression of VGCCs has been linked to various disease conditions. Here, we provide an overview of the mechanisms that control the trafficking of VGCCs to and from the plasma membrane, and discuss their implication in pathophysiological conditions and their potential as therapeutic targets.

• Keywords
• Stac adaptor proteins, ancillary subunit, calcium channels, glycosylation, trafficking, ubiquitination, voltage-gated calcium channels,
• Publication type
• Journal Article MeSH
• Review MeSH

T-type calcium channels are key contributors to neuronal physiology where they shape electrical activity of nerve cells and contribute to the release of neurotransmitters. Enhanced T-type channel expression has been causally linked to a number of pathological conditions including peripheral painful diabetic neuropathy. Recently, it was demonstrated that asparagine-linked glycosylation not only plays an essential role in regulating cell surface expression of Cav3.2 channels, but may also support glucose-dependent potentiation of T-type currents. However, the underlying mechanisms by which N-glycosylation and glucose levels modulate the expression of T-type channels remain elusive. In the present study, we show that site-specific N-glycosylation of Cav3.2 is essential to stabilize expression of the channel at the plasma membrane. In contrast, elevated external glucose concentration appears to potentiate intracellular forward trafficking of the channel to the cell surface, resulting in an increased steady-state expression of the channel protein at the plasma membrane. Collectively, our study indicates that glucose and N-glycosylation act in concert to control the expression of Cav3.2 channels, and that alteration of these mechanisms may contribute to the altered expression of T-type channels in pathological conditions.

• Keywords
• Calcium channel, Cav3.2, Glucose, N-glycosylation, T-type channel, Trafficking,
• MeSH
• Asparagine metabolism   MeSH
• Cell Membrane metabolism   MeSH
• Glucose pharmacology   MeSH
• Glycosylation MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Protein Processing, Post-Translational * MeSH
• Protein Transport drug effects   MeSH
• Calcium Channels, T-Type genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Asparagine MeSH
• Glucose MeSH
• Calcium Channels, T-Type MeSH

Low-voltage-activated T-type calcium channels are essential contributors to neuronal physiology where they play complex yet fundamentally important roles in shaping intrinsic excitability of nerve cells and neurotransmission. Aberrant neuronal excitability caused by alteration of T-type channel expression has been linked to a number of neuronal disorders including epilepsy, sleep disturbance, autism, and painful chronic neuropathy. Hence, there is increased interest in identifying the cellular mechanisms and actors that underlie the trafficking of T-type channels in normal and pathological conditions. In the present study, we assessed the ability of Stac adaptor proteins to associate with and modulate surface expression of T-type channels. We report the existence of a Cav3.2/Stac1 molecular complex that relies on the binding of Stac1 to the amino-terminal region of the channel. This interaction potently modulates expression of the channel protein at the cell surface resulting in an increased T-type conductance. Altogether, our data establish Stac1 as an important modulator of T-type channel expression and provide new insights into the molecular mechanisms underlying the trafficking of T-type channels to the plasma membrane.

• Keywords
• Cav3.2 channel, Stac adaptor protein, T-type calcium channel, trafficking,
• MeSH
• Cell Membrane metabolism   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Nerve Tissue Proteins metabolism   physiology   MeSH
• Calcium Channels, T-Type metabolism   physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• CACNA1H protein, human MeSH Browser
• Nerve Tissue Proteins MeSH
• Calcium Channels, T-Type MeSH

Low-voltage-gated T-type calcium channels are expressed throughout the nervous system where they play an essential role in shaping neuronal excitability. Defects in T-type channel expression have been linked to various neuronal disorders including neuropathic pain and epilepsy. Currently, little is known about the cellular mechanisms controlling the expression and function of T-type channels. Asparagine-linked glycosylation has recently emerged as an essential signaling pathway by which the cellular environment can control expression of T-type channels. However, the role of N-glycans in the conducting function of T-type channels remains elusive. In the present study, we used human Cav3.2 glycosylation-deficient channels to assess the role of N-glycosylation on the gating of the channel. Patch-clamp recordings of gating currents revealed that N-glycans attached to hCav3.2 channels have a minimal effect on the functioning of the channel voltage-sensor. In contrast, N-glycosylation on specific asparagine residues may have an essential role in the conducting function of the channel by enhancing the channel permeability and / or the pore opening of the channel. Our data suggest that modulation of N-linked glycosylation of hCav3.2 channels may play an important physiological role, and could also support the alteration of T-type currents observed in disease states.

• Keywords
• Cav3.2, T-type channel, calcium channel, gating, glycosylation,
• MeSH
• Asparagine metabolism   MeSH
• Electrophysiological Phenomena MeSH
• Ion Channel Gating MeSH
• Glycosylation MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Permeability MeSH
• Calcium Channels, T-Type chemistry   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Asparagine MeSH
• CACNA1H protein, human MeSH Browser
• Calcium Channels, T-Type MeSH