Omega-conotoxin inhibits the acute activation of tyrosine hydroxylase and the stimulation of norepinephrine release by potassium depolarization of sympathetic nerve endings.
Increased Ca2+ influx serves as a signal that initiates multiple biochemical and physiological events in neurons following depolarization. The most widely studied of these phenomena is the release of neurotransmitters. In sympathetic neurons, depolarization also increases the rate of synthesis of the transmitter norepinephrine (NE), via an activation of the enzyme tyrosine hydroxylase (TH), and this effect also seems to involve Ca2+ entry. We have examined whether the mechanism of Ca2+ entry relevant to TH activation is via voltage-sensitive Ca2+ channels and, if so, whether the type of Ca2+ channel involved is the same as that involved in the stimulation of NE release. We have investigated the isolated rat iris, allowing us to examine transmitter biosynthesis and release in sympathetic nerve terminals in the absence of sympathetic cell bodies and dendrites. Potassium depolarization produced a three- to fivefold increase in TH activity and an approximately 100-fold increase in NE release. Both effects were dependent on Ca2+ being present in the extracellular medium, and both were inhibited by omega-conotoxin (1 microM), which inhibits N-type voltage-sensitive Ca2+ channels. In contrast, the dihydropyridine nimodipine (1-3 microM), which blocks L-type Ca2+ channels, had no effect on either measure. These data support the hypothesis that increases in NE biosynthesis and release in sympathetic nerve terminals during periods of depolarization are both initiated by an influx of Ca2+ through voltage-sensitive Ca2+ channels and that a similar type of Ca2+ channel is involved in both processes.
Rittenhouse
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AR
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
Zigmond
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D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D007498:Iris / Q000187:drug effects / Q000294:innervation; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D018727:Muscarinic Antagonists; D009411:Nerve Endings / Q000187:drug effects / Q000502:physiology*; D018733:Nicotinic Antagonists; D009553:Nimodipine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D020960:omega-Conotoxins
D015220:Calcium Channels; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D010456:Peptides, Cyclic; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D020960:omega-Conotoxins; C053423:Conus magus toxin; D009553:Nimodipine; D014446:Tyrosine 3-Monooxygenase; D008274:Magnesium; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine