Differential expression of T-type calcium channels in P/Q-type calcium channel mutant mice with ataxia and absence epilepsy

2005 ◽  
Vol 62 (3) ◽  
pp. 352-360 ◽  
Author(s):  
Sang-Soep Nahm ◽  
Ki-Yoon Jung ◽  
Melanie Krause Enger ◽  
William H. Griffith ◽  
Louise C. Abbott
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Differential Expression ◽  
Absence Epilepsy ◽  
Mutant Mice

scholarly journals Absence Epilepsy in Tottering Mutant Mice Is Associated with Calcium Channel Defects

Cell ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 607-617 ◽  
Author(s):  
Colin F Fletcher ◽  
Cathleen M Lutz ◽  
T.Norene O'Sullivan ◽  
John D Shaughnessy ◽  
Richard Hawkes ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Absence Epilepsy ◽  
Mutant Mice

scholarly journals Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties

2015 ◽  
Vol 112 (44) ◽  
pp. 13705-13710 ◽  
Author(s):  
Iulia Blesneac ◽  
Jean Chemin ◽  
Isabelle Bidaud ◽  
Sylvaine Huc-Brandt ◽  
Franck Vandermoere ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Low Voltage ◽  
Absence Epilepsy ◽  
Mammalian Brain ◽  
Systematic Analysis ◽  
Dynamic Regulation ◽  
Major Mechanism ◽  
Voltage Dependent

Phosphorylation is a major mechanism regulating the activity of ion channels that remains poorly understood with respect to T-type calcium channels (Cav3). These channels are low voltage-activated calcium channels that play a key role in cellular excitability and various physiological functions. Their dysfunction has been linked to several neurological disorders, including absence epilepsy and neuropathic pain. Recent studies have revealed that T-type channels are modulated by a variety of serine/threonine protein kinase pathways, which indicates the need for a systematic analysis of T-type channel phosphorylation. Here, we immunopurified Cav3.2 channels from rat brain, and we used high-resolution MS to construct the first, to our knowledge, in vivo phosphorylation map of a voltage-gated calcium channel in a mammalian brain. We identified as many as 34 phosphorylation sites, and we show that the vast majority of these sites are also phosphorylated on the human Cav3.2 expressed in HEK293T cells. In patch-clamp studies, treatment of the channel with alkaline phosphatase as well as analysis of dephosphomimetic mutants revealed that phosphorylation regulates important functional properties of Cav3.2 channels, including voltage-dependent activation and inactivation and kinetics. We also identified that the phosphorylation of a locus situated in the loop I-II S442/S445/T446 is crucial for this regulation. Our data show that Cav3.2 channels are highly phosphorylated in the mammalian brain and establish phosphorylation as an important mechanism involved in the dynamic regulation of Cav3.2 channel gating properties.

Calcium Channels Genes and Their Epilepsy Phenotypes

2021 ◽  
Author(s):  
Giulio Pulvirenti ◽  
Martina Caccamo ◽  
Manuela Lo Bianco ◽  
Marina Mazzurco ◽  
Elena R. Praticò ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Gene Mutations ◽  
Febrile Seizures ◽  
Autism Spectrum ◽  
Absence Epilepsy ◽  
Treatment Recommendation ◽  
Spinocerebellar Ataxia Type ◽  
Epilepsy Syndrome ◽  
Channel Gene

AbstractCalcium (Ca2+) channel gene mutations play an important role in the pathogenesis of neurological episodic disorders like epilepsy. CACNA1A and CACNA1H genes are involved in the synthesis of calcium channels. Mutations in the α1A subunit of the P/Q type voltage-gated calcium channel gene (CACNA1A) located in 19p13.13, which encodes for the transmembrane pore-forming subunit of CAV2.1 voltage-dependent calcium channel, have been correlated to a large clinical spectrum of epilepsy such as idiopathic genetic epilepsy, early infantile epilepsy, and febrile seizures. Moreover, CACNA1A mutations have been demonstrated to be involved in spinocerebellar ataxia type 6, familiar hemiplegic migraine, episodic ataxia type 2, early-onset encephalopathy, and hemiconvulsion–hemiplegia epilepsy syndrome. This wide phenotype heterogeneity associated with CACNA1A mutations is correlated to different clinical and electrophysiological manifestations. CACNA1H gene, located in 16p13.3, encodes the α1H subunit of T-type calcium channel, expressing the transmembrane pore-forming subunit Cav3.2. Despite data still remain controversial, it has been identified as an important gene whose mutations seem strictly related to the pathogenesis of childhood absence epilepsy and other generalized epilepsies. The studied variants are mainly gain-of-function, hence responsible for an increase in neuronal susceptibility to seizures. CACNA1H mutations have also been associated with autism spectrum disorder and other behavior disorders. More recently, also amyotrophic lateral sclerosis has been related to CACNA1H alterations. The aim of this review, other than describe the CACNA1A and CACNA1H gene functions, is to identify mutations reported in literature and to analyze their possible correlations with specific epileptic disorders, purposing to guide an appropriate medical treatment recommendation.

scholarly journals Caenorhabditis elegans Junctophilin has tissue-specific functions and regulates neurotransmission with extended-synaptotagmin

Genetics ◽  
2021 ◽  
Author(s):  
Christopher A Piggott ◽  
Zilu Wu ◽  
Stephen Nurrish ◽  
Suhong Xu ◽  
Joshua M Kaplan ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Tissue Specific ◽  
Voltage Gated ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Pharyngeal Muscles ◽  
Membrane Contact ◽  
Null Mutants

Abstract The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understanding in vivo functions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the sole C. elegans junctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions. jph-1 null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 co-localizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68/RyR calcium channel, and is required for animal movement. In neurons, JPH-1 co-localizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) in soma, and is present near presynaptic release sites. Interestingly, jph-1 and esyt-2 null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-2 have antagonistic roles in neuromuscular synaptic transmission. Additionally, we find an unexpected cell non-autonomous effect of jph-1 in axon regrowth after injury. Genetic double mutant analysis suggests that jph-1 functions in overlapping pathways with two PM-localized voltage-gated calcium channels, egl-19 and unc-2, and unc-68/RyR for animal health and development. Finally, we show that jph-1 regulates the colocalization of EGL-19 and UNC-68 and that unc-68/RyR is required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channels in vivo.

scholarly journals Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal

2019 ◽  
Vol 216 (5) ◽  
pp. 250-253 ◽  
Author(s):  
Paul J. Harrison ◽  
Elizabeth M. Tunbridge ◽  
Annette C. Dolphin ◽  
Jeremy Hall
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Psychiatric Disorders ◽  
Calcium Channel Blockers ◽  
Channel Blockers ◽  
Risk Genes ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Voltage Gated Calcium Channel ◽  
Second Use

SummaryWe reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes. Third, research shows there is an opportunity for brain-selective CCBs, which are better suited to psychiatric indications.

scholarly journals Courtship and Visual Defects of cacophony Mutants Reveal Functional Complexity of a Calcium-Channel α1 Subunit in Drosophila

Genetics ◽  
1998 ◽  
Vol 149 (3) ◽  
pp. 1407-1426 ◽  
Author(s):  
Lee A Smith ◽  
Alexandre A Peixoto ◽  
Elena M Kramer ◽  
Adriana Villella ◽  
Jeffrey C Hall
Keyword(s):  
Alternative Splicing ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Stop Codon ◽  
Biological Functions ◽  
Visual Defects ◽  
Transcript Diversity ◽  
Functional Complexity ◽  
Α1 Subunit ◽  
Subtle Abnormality

Abstract We show by molecular analysis of behavioral and physiological mutants that the Drosophila Dmca1A calcium-channel α1 subunit is encoded by the cacophony (cac) gene and that nightblind-A and lethal(1)L13 mutations are allelic to cac with respect to an expanded array of behavioral and physiological phenotypes associated with this gene. The cacS mutant, which exhibits defects in the patterning of courtship lovesong and a newly revealed but subtle abnormality in visual physiology, is mutated such that a highly conserved phenylalanine (in one of the quasi-homologous intrapolypeptide regions called IIIS6) is replaced by isoleucine. The cacH18 mutant exhibits defects in visual physiology (including complete unresponsiveness to light in certain genetic combinations) and visually mediated behaviors; this mutant (originally nbAH18) has a stop codon in an alternative exon (within the cac ORF), which is differentially expressed in the eye. Analysis ofthe various courtship and visual phenotypes associated with this array ofcac mutants demonstrates that Dmca1A calcium channels mediate multiple, separable biological functions; these correlate in part with transcript diversity generated via alternative splicing.

Role of calcium channels and protein kinase C for release of norepinephrine and neuropeptide Y

1990 ◽  
Vol 259 (5) ◽  
pp. R925-R930
Author(s):  
M. Haass ◽  
C. Forster ◽  
G. Richardt ◽  
R. Kranzhofer ◽  
A. Schomig
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Neuropeptide Y ◽  
Nerve Fibers ◽  
Extracellular Calcium ◽  
Minor Effect ◽  
Kinase C

The role of calcium for the release of norepinephrine (NE, determined by high-pressure liquid chromatography) and neuropeptide Y (NPY, determined by radioimmunoassay) was investigated in guinea pig perfused hearts with intact sympathetic innervation. In the presence of extracellular calcium (1.85 mM), electrical stimulation of the left stellate ganglion (12 Hz, 1 min) induced a closely related release of NE and NPY with the molar ratio of approximately 400-600 (NE) to 1 (NPY). The stimulation-evoked overflow of both transmitters was dependent from the extracellular calcium concentration and was almost completely suppressed by calcium-free perfusion. The corelease of both transmitters was not affected by the L-type calcium channel blocker felodipine (1-10 microM). However, the overflow of NE and NPY was markedly attenuated by the unselective calcium antagonist flunarizine (1-10 microM) and completely prevented by the neuronal (N-type) calcium channel blockers omega-conotoxin (1-100 nM) and cadmium chloride (10-100 microM), indicating a key role for N-type calcium channels in the exocytotic release of transmitters from cardiac sympathetic nerve fibers. Possibly due to unspecific actions, such as interference with sodium channels or uptake1-blocking properties, the phenylalkylamines verapamil (0.01-10 microM) and gallopamil (1-10 microM) reduced NPY overflow with only a minor effect on NE overflow. The stimulation-induced transmitter release was increased up to twofold by activation of protein kinase C (phorbol 12-myristate 13-acetate, 3 nM-3 microM) and completely suppressed by inhibition of protein kinase C (polymyxin B, 100 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Insulation of the conduction pathway of muscle transverse tubule calcium channels from the surface charge of bilayer phospholipid.

1986 ◽  
Vol 87 (6) ◽  
pp. 933-953 ◽  
Author(s):  
R Coronado ◽  
H Affolter
Keyword(s):  
Ionic Strength ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Surface Charge ◽  
Single Channel ◽  
Small Surface ◽  
Bilayer Lipid ◽  
Sodium Conductance ◽  
Conduction Pathway ◽  
Lipid Surface

Functional calcium channels present in purified skeletal muscle transverse tubules were inserted into planar phospholipid bilayers composed of the neutral lipid phosphatidylethanolamine (PE), the negatively charged lipid phosphatidylserine (PS), and mixtures of both. The lengthening of the mean open time and stabilization of single channel fluctuations under constant holding potentials was accomplished by the use of the agonist Bay K8644. It was found that the barium current carried through the channel saturates as a function of the BaCl2 concentration at a maximum current of 0.6 pA (at a holding potential of 0 mV) and a half-saturation value of 40 mM. Under saturation, the slope conductance of the channel is 20 pS at voltages more negative than -50 mV and 13 pS at a holding potential of 0 mV. At barium concentrations above and below the half-saturation point, the open channel currents were independent of the bilayer mole fraction of PS from XPS = 0 (pure PE) to XPS = 1.0 (pure PS). It is shown that in the absence of barium, the calcium channel transports sodium or potassium ions (P Na/PK = 1.4) at saturating rates higher than those for barium alone. The sodium conductance in pure PE bilayers saturates as a function of NaCl concentration, following a curve that can be described as a rectangular hyperbola with a half-saturation value of 200 mM and a maximum conductance of 68 pS (slope conductance at a holding potential of 0 mV). In pure PS bilayers, the sodium conductance is about twice that measured in PE at concentrations below 100 mM NaCl. The maximum channel conductance at high ionic strength is unaffected by the lipid charge. This effect at low ionic strength was analyzed according to J. Bell and C. Miller (1984. Biophysical Journal. 45:279-287) and interpreted as if the conduction pathway of the calcium channel were separated from the bilayer lipid by approximately 20 A. This distance thereby effectively insulates the ion entry to the channel from the bulk of the bilayer lipid surface charge. Current vs. voltage curves measured in NaCl in pure PE and pure PS show that similarly small surface charge effects are present in both inward and outward currents. This suggests that the same conduction insulation is present at both ends of the calcium channel.

scholarly journals Gating Effects of Mutations in the Cav3.2 T-type Calcium Channel Associated with Childhood Absence Epilepsy

2004 ◽  
Vol 279 (11) ◽  
pp. 9681-9684 ◽  
Author(s):  
Houman Khosravani ◽  
Christophe Altier ◽  
Brett Simms ◽  
Kevin S. Hamming ◽  
Terrance P. Snutch ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Absence Epilepsy ◽  
Childhood Absence Epilepsy
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