Faculty Opinions recommendation of Cell-specific alternative splicing increases calcium channel current density in the pain pathway.

2004 ◽  
Author(s):  
Annette Dolphin
Keyword(s):  
Alternative Splicing ◽  
Calcium Channel ◽  
Current Density ◽  
Channel Current ◽  
Pain Pathway ◽  
Specific Alternative

scholarly journals Cell-Specific Alternative Splicing Increases Calcium Channel Current Density in the Pain Pathway

Neuron ◽  
2004 ◽  
Vol 41 (1) ◽  
pp. 127-138 ◽  
Author(s):  
Thomas J Bell ◽  
Christopher Thaler ◽  
Andrew J Castiglioni ◽  
Thomas D Helton ◽  
Diane Lipscombe
Keyword(s):  
Alternative Splicing ◽  
Calcium Channel ◽  
Current Density ◽  
Channel Current ◽  
Pain Pathway ◽  
Specific Alternative

scholarly journals Cell-specific exon methylation and CTCF binding in neurons regulates calcium ion channel splicing and function

2019 ◽  
Author(s):  
Eduardo Javier Lopez Soto ◽  
Diane Lipscombe
Keyword(s):  
Alternative Splicing ◽  
Peripheral Nerve ◽  
Calcium Channel ◽  
Nerve Injury ◽  
Calcium Ion ◽  
Peripheral Nerve Injury ◽  
Ctcf Binding ◽  
Channel Gene ◽  
Specific Alternative ◽  
Opioid Sensitivity

SummaryCell-specific alternative splicing modulates myriad cell functions and this process is disrupted in disease. The mechanisms governing alternative splicing are known for relatively few genes and typically focus on RNA splicing factors. In sensory neurons, cell-specific alternative splicing of the presynaptic voltage-gated calcium channel Cacna1b gene modulates opioid sensitivity. How this splicing is regulated has remained unknown. We find that cell-specific exon DNA hypomethylation permits binding of CTCF, the master regulator of chromatin structure in mammals, which, in turn, controls splicing in noxious heat-sensing nociceptors.Hypomethylation of an alternative exon specifically in nociceptors allows for CTCF binding, and expression of CaV2.2 channels with increased opioid sensitivity. Following nerve injury, exon methylation is increased, and splicing is disrupted. Our studies define the molecular mechanisms of cell-specific alternative splicing of a functionally validated exon in normal and disease states – and reveal a potential target for the treatment of chronic pain.HighlightsThe molecular basis of cell-specific splicing of a synaptic calcium channel gene.Splicing controlled by cell-specific exon hypomethylation and CTCF binding.Peripheral nerve injury disrupts exon hypomethylation and splicing.Targeted demethylation of exon by dCAS9-TET modifies alternative splicing.GRAPHICAL ABSTRACTCell-specific epigenetic modifications in a synaptic calcium ion channel gene controls cell-specific splicing in normal and neuropathic pain.In naïve animals, in most neurons, Cacna1b e37a locus is hipermethylated (5-mC) and CTCF does not bind this locus. During splicing, e37a is skipped and Cacna1b mRNAs include e37b. In contrast, in Trpv1-lineage neurons, Cacna1b e37a locus is hypomethylated and is permissive for CTCF binding. CTCF promotes e37a inclusion and both Cacna1b e37a and e37b mRNAs are expressed. E37a confers strong sensitivity to the Cav2.2 channel to inhibition by μ-opioid receptors (μOR). Morphine is more effective at inhibiting e37a-containing Cav2.2 channels. After peripheral nerve injury that results in pathological pain, methylation level of Cacna1b e37a locus is increased, CTCF binding is impaired, and Cacna1b e37a mRNA levels are decreased. This disrupted splicing pattern is associated with reduced efficacy of morphine in vivo.

scholarly journals Cholesterol increases the L-type voltage-sensitive calcium channel current in arterial smooth muscle cells.

1992 ◽  
Vol 71 (4) ◽  
pp. 1008-1014 ◽  
Author(s):  
L Sen ◽  
R A Bialecki ◽  
E Smith ◽  
T W Smith ◽  
W S Colucci
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Calcium Channel ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
Channel Current ◽  
Arterial Smooth Muscle Cells

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.

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