Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Alternative Splicing / drug effects*
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Analgesics, Opioid / pharmacology*
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Animals
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Animals, Newborn
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Calcitonin Gene-Related Peptide / metabolism
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Calcium Channel Blockers / pharmacology
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Calcium Channels, N-Type / genetics*
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Disease Models, Animal
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Drug Interactions
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Electric Stimulation / methods
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Embryo, Mammalian
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Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
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Exons / genetics
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / metabolism
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Gene Expression Regulation / drug effects
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Hyperalgesia / drug therapy
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Hyperalgesia / genetics
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Hyperalgesia / pathology
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Lectins / metabolism
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Male
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Morphine / pharmacology*
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Patch-Clamp Techniques
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RNA, Messenger / metabolism
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Spinal Cord / cytology
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Spinal Cord / drug effects*
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Spinal Cord / physiology
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omega-Conotoxin GVIA / pharmacology
Substances
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Analgesics, Opioid
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Cacna1b protein, mouse
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Calcium Channel Blockers
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Calcium Channels, N-Type
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Lectins
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RNA, Messenger
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Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
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Morphine
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omega-Conotoxin GVIA
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Calcitonin Gene-Related Peptide