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.

• Klíčová slova
• Calcium channels, Channelosome, Ion channels, T-type channels,
• MeSH
• blokátory kalciových kanálů MeSH
• neurony metabolismus   MeSH
• vápník * metabolismus   MeSH
• vápníkové kanály - typ T * metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• blokátory kalciových kanálů MeSH
• vápník * MeSH
• vápníkové kanály - typ T * MeSH

Missense mutations in the human secretary carrier-associated membrane protein 5 (SCAMP5) cause a variety of neurological disorders including neurodevelopmental delay, epilepsy, and Parkinson's disease. We recently documented the importance of SCAMP2 in the regulation of T-type calcium channel expression in the plasma membrane. Here, we show that similar to SCAMP2, the co-expression of SCAMP5 in tsA-201 cells expressing recombinant Cav3.1, Cav3.2, and Cav3.3 channels nearly abolished whole-cell T-type currents. Recording of intramembrane charge movements revealed that SCAMP5-induced inhibition of T-type currents is primarily caused by the reduced expression of functional channels in the plasma membrane. Moreover, we show that SCAMP5-mediated downregulation of Cav3.2 channels is essentially preserved with disease-causing SCAMP5 R91W and G180W mutations. Hence, this study extends our previous findings with SCAMP2 and indicates that SCAMP5 also contributes to repressing the expression of T-type channels in the plasma membrane.

• Klíčová slova
• Calcium channels, Channelopathy, Ion channels, SCAMP5, Secretory carrier-associated membrane protein 5, T-type channels,
• MeSH
• buněčná membrána MeSH
• down regulace MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mutace MeSH
• vápníkové kanály - typ T * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• membránové proteiny MeSH
• SCAMP5 protein, human MeSH Prohlížeč
• vápníkové kanály - typ T * MeSH

Low-voltage-activated T-type Ca2+ channels are key regulators of neuronal excitability both in the central and peripheral nervous systems. Therefore, their recruitment at the plasma membrane is critical in determining firing activity patterns of nerve cells. In this study, we report the importance of secretory carrier-associated membrane proteins (SCAMPs) in the trafficking regulation of T-type channels. We identified SCAMP2 as a novel Cav3.2-interacting protein. In addition, we show that co-expression of SCAMP2 in mammalian cells expressing recombinant Cav3.2 channels caused an almost complete drop of the whole cell T-type current, an effect partly reversed by single amino acid mutations within the conserved cytoplasmic E peptide of SCAMP2. SCAMP2-induced downregulation of T-type currents was also observed in cells expressing Cav3.1 and Cav3.3 channel isoforms. Finally, we show that SCAMP2-mediated knockdown of the T-type conductance is caused by the lack of Cav3.2 expression at the cell surface as evidenced by the concomitant loss of intramembrane charge movement without decrease of total Cav3.2 protein level. Taken together, our results indicate that SCAMP2 plays an important role in the trafficking of Cav3.2 channels at the plasma membrane.

• Klíčová slova
• Calcium channels, Cav3.2 channels, Ion channels, SCAMP2, Secretory carrier-associated membrane protein 2, T-type channels, Trafficking,
• MeSH
• buněčná membrána metabolismus   MeSH
• membránové proteiny metabolismus   MeSH
• neurony metabolismus   MeSH
• savci metabolismus   MeSH
• transportní proteiny metabolismus   MeSH
• vápník metabolismus   MeSH
• vápníkové kanály - typ T * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• membránové proteiny MeSH
• transportní proteiny MeSH
• vápník MeSH
• vápníkové kanály - typ T * 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.

• Klíčová slova
• ALS, Amyotrophic lateral sclerosis, Biophysics, CACNA1H, Calcium channel, Cav3.2 channel, Motor neuron disease, Mutation, T-type channel,
• MeSH
• amyotrofická laterální skleróza * genetika   MeSH
• dominantní geny MeSH
• genetická predispozice k nemoci * MeSH
• genetické asociační studie * MeSH
• heterozygot MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mutace * genetika   MeSH
• sekvence aminokyselin MeSH
• sekvenování celého genomu MeSH
• strukturní homologie proteinů MeSH
• vápníkové kanály - typ T * chemie   genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CACNA1H protein, human MeSH Prohlížeč
• vápníkové kanály - typ T * 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.

• Klíčová slova
• aldosteronism, amyotrophic lateral sclerosis, autism spectrum disorders, calcium channels, cav3 channels, channelopathies, epilepsy, mutation, schizophrenia, t-type channels,
• MeSH
• kanálopatie genetika   metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• vápníkové kanály genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• vápníkové kanály 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.

• Klíčová slova
• Stac adaptor proteins, ancillary subunit, calcium channels, glycosylation, trafficking, ubiquitination, voltage-gated calcium channels,
• Publikační typ
• časopisecké články MeSH
• přehledy 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.

• Klíčová slova
• Calcium channel, Cav3.2, Glucose, N-glycosylation, T-type channel, Trafficking,
• MeSH
• asparagin metabolismus   MeSH
• buněčná membrána metabolismus   MeSH
• glukosa farmakologie   MeSH
• glykosylace MeSH
• HEK293 buňky MeSH
• lidé MeSH
• posttranslační úpravy proteinů * MeSH
• transport proteinů účinky léků   MeSH
• vápníkové kanály - typ T genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• asparagin MeSH
• glukosa MeSH
• vápníkové kanály - typ T MeSH