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Opioid inhibition of N-type Ca2+ channels and spinal analgesia couple to alternative splicing.

Nature neuroscience | Oct 29, 2010

Alternative pre-mRNA splicing occurs extensively in the nervous systems of complex organisms, including humans, considerably expanding the potential size of the proteome. Cell-specific alternative pre-mRNA splicing is thought to optimize protein function for specialized cellular tasks, but direct evidence for this is limited. Transmission of noxious thermal stimuli relies on the activity of N-type Ca(V)2.2 calcium channels in nociceptors. Using an exon-replacement strategy in mice, we show that mutually exclusive splicing patterns in the Ca(V)2.2 gene modulate N-type channel function in nociceptors, leading to a change in morphine analgesia. Exon 37a (e37a) enhances μ-opioid receptor-mediated inhibition of N-type calcium channels by promoting activity-independent inhibition. In the absence of e37a, spinal morphine analgesia is weakened in vivo but the basal response to noxious thermal stimuli is not altered. Our data suggest that highly specialized, discrete cellular responsiveness in vivo can be attributed to alternative splicing events regulated at the level of individual neurons.

Pubmed ID: 20852623 RIS Download

Mesh terms: Alternative Splicing | Analgesics, Opioid | Animals | Animals, Newborn | Calcitonin Gene-Related Peptide | Calcium Channel Blockers | Calcium Channels, N-Type | Disease Models, Animal | Drug Interactions | Electric Stimulation | Embryo, Mammalian | Enkephalin, Ala(2)-MePhe(4)-Gly(5)- | Exons | Ganglia, Spinal | Gene Expression Regulation | Hyperalgesia | Lectins | Male | Membrane Potentials | Mice | Mice, Inbred C57BL | Mice, Transgenic | Morphine | Patch-Clamp Techniques | RNA, Messenger | Spinal Cord | omega-Conotoxin GVIA

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Associated grants

  • Agency: NCRR NIH HHS, Id: P20RR015578
  • Agency: NINDS NIH HHS, Id: R01 NS029967-17
  • Agency: NCRR NIH HHS, Id: P20 RR015578-049001
  • Agency: NINDS NIH HHS, Id: F31 NS066702-02
  • Agency: NINDS NIH HHS, Id: F31 NS066702
  • Agency: NINDS NIH HHS, Id: R01 NS055251-06
  • Agency: NINDS NIH HHS, Id: R01 NS029967
  • Agency: NCRR NIH HHS, Id: P20 RR015578
  • Agency: NINDS NIH HHS, Id: R01NS055251
  • Agency: NINDS NIH HHS, Id: F31NS066702
  • Agency: NINDS NIH HHS, Id: R01 NS055251

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pClamp

Software suite for electrophysiology data acquisition and analysis by Molecular Devices. Used for the control and recording of voltage clamp, current clamp, and patch clamp experiments. The software suite consists of Clampex 11 Software for data acquisition, AxoScope 11 Software for background recording, Clampfit 11 Software for data analysis, and optional Clampfit Advanced Analysis Module for sophisticated and streamlined analysis.

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