Fast, local signal transduction between the mu opioid receptor and Ca2+ channels.
We used patch-clamp methods to describe signal transduction between the mu opioid receptor, the binding site for morphine, and high-threshold Ca2+ channels in dorsal root ganglion (DRG) sensory neurons from adult rats. Opioid signaling persists in excised membrane patches, and an activated opioid receptor can only inhibit nearby Ca2+ channels; thus, no readily diffusible second-messenger molecule mediates between the mu receptor and Ca2+ channels. Inhibition of Ca2+ channels begins several hundred msec after application of opioid and it is maximal by 5 sec; this is faster than typical phosphorylation cascades. Blockade of the known serine-threonine kinases and phosphatases does not affect this opioid signaling and, as shown previously by Seward et al. (1991) and Moises et al. (1994a), pertussis toxin eliminates virtually all of the effect. Inhibited channels can open, but their half-activation voltage is unphysiologically positive. The link between the mu receptor and Ca2+ channels is clearly unlike the protein kinase C-dependent paths that couple mu receptors to NMDA channels in dorsal horn neurons (Chen and Huang, 1991) and alpha-adrenergic receptors to Ca2+ channels in DRG neurons (Diversé-Pierluissi and Dunlap, 1993). The rapid kinetics and tight localization of the signaling path are properties expected if receptor and channel are linked directly by a G-protein, but these properties do not constitute proof of such a pathway.
Wilding
T J
TJ
Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Womack
M D
MD
McCleskey
E W
EW
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology*; D004988:Ethers, Cyclic / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000502:physiology*; D007700:Kinetics; D052998:Microcystins; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D019319:Okadaic Acid; D018408:Patch-Clamp Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D037342:Pertussis Toxin; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D051381:Rats; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine; D013997:Time Factors; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000470:Alkaloids; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004745:Enkephalins; D004988:Ethers, Cyclic; D052998:Microcystins; D010456:Peptides, Cyclic; D047428:Protein Kinase Inhibitors; D017450:Receptors, Opioid, mu; D010566:Virulence Factors, Bordetella; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019319:Okadaic Acid; D003994:Bucladesine; C078588:microcystin; D037342:Pertussis Toxin; D010749:Phosphoprotein Phosphatases; D019311:Staurosporine; D015056:1-Methyl-3-isobutylxanthine