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
- absentní epilepsie genetika MeSH
- kalnexin metabolismus MeSH
- krysa rodu rattus MeSH
- missense mutace * MeSH
- modely nemocí na zvířatech MeSH
- mutantní proteiny genetika metabolismus MeSH
- transport proteinů MeSH
- vápníkové kanály - typ T genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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.
- MeSH
- buněčná membrána metabolismus MeSH
- HEK293 buňky MeSH
- lidé MeSH
- proteiny nervové tkáně metabolismus fyziologie MeSH
- vápníkové kanály - typ T metabolismus fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Neuronal voltage-gated calcium channels have evolved as one of the most important players for calcium entry into presynaptic endings responsible for the release of neurotransmitters. In turn, and to fine-tune synaptic activity and neuronal communication, numerous neurotransmitters exert a potent negative feedback over the calcium signal provided by G protein-coupled receptors. This regulation pathway of physiologic importance is also extensively exploited for therapeutic purposes, for instance in the treatment of neuropathic pain by morphine and other μ-opioid receptor agonists. However, despite more than three decades of intensive research, important questions remain unsolved regarding the molecular and cellular mechanisms of direct G protein inhibition of voltage-gated calcium channels. In this study, we revisit this particular regulation and explore new considerations.
- MeSH
- blokátory kalciových kanálů farmakologie MeSH
- konformace proteinů MeSH
- lidé MeSH
- neurony metabolismus MeSH
- presynaptické terminály metabolismus MeSH
- proteiny vázající GTP - beta-podjednotky metabolismus MeSH
- proteiny vázající GTP - gama-podjednotky metabolismus MeSH
- proteiny vázající GTP metabolismus MeSH
- receptory spřažené s G-proteiny metabolismus MeSH
- vápníkové kanály chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- kognitivní poruchy patofyziologie MeSH
- pohlavní dimorfismus * MeSH
- poruchy paměti patofyziologie MeSH
- stárnutí fyziologie psychologie MeSH
- vápníkové kanály - typ L metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- komentáře MeSH
- práce podpořená grantem MeSH
Commentary to: Functional changes in pyramidal neurons in the chronic methamphetamine-treated rat. (Gen. Physiol. Biophys. 2015, pp.5-12).
- MeSH
- methamfetamin aplikace a dávkování MeSH
- neurony patologie MeSH
- pyramidové buňky patologie MeSH
- pyriformní kůra patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- komentáře MeSH
- práce podpořená grantem MeSH
- úvodníky MeSH
Neuronal abnormalities in neurodegenerative disorders such as Huntington disease, Alzheimer disease or Parkinson disease have been the primary focus of decades of research. However, increasing evidences indicate that glial cells and more specifically astrocytes could be as important players as their big brother. It is now particularly evident in Huntington disease where astrocytal potassium channels have emerged as a likely key factor in the pathogenesis of the disease.
- Publikační typ
- časopisecké články MeSH
Perhaps one of the most remarkable features of T-type calcium channels is their low-threshold of activation that makes these channels important candidates for calcium entry near the resting membrane potential of neurons. Hence, they mediate low-threshold burst discharges that occur during different forms of neuronal rhythmogenesis, but play also important roles in sensory transmission, as well as hormone and neurotransmitter release. Additionally, they have been implicated in an increasing number of neuronal pathologies including neuropathy, autism spectrum disorders and some forms of epilepsy. More recently, an implication of T-type calcium channel in the processing of Amyloid Precursor Protein was documented, with possible implication in the pathogenesis of Alzheimer's disease.
- Publikační typ
- časopisecké články MeSH
