Role of N- and L-type calcium channels in depolarization-induced activation of tyrosine hydroxylase and release of norepinephrine by sympathetic cell bodies and nerve terminals.
Multiple types of voltage-activated calcium (Ca(2+)) channels are present in all nerve cells examined so far; however, the underlying functional consequences of their presence is often unclear. We have examined the contribution of Ca(2+) influx through N- and L- type voltage-activated Ca(2+) channels in sympathetic neurons to the depolarization-induced activation of tyrosine hydroxylase (TH), the rate-limiting enzyme in norepinephrine (NE) synthesis, and the depolarization-induced release of NE. Superior cervical ganglia (SCG) were decentralized 4 days prior to their use to eliminate the possibility of indirect effects of depolarization via preganglionic nerve terminals. The presence of both omega-conotoxin GVIA (1 microM), a specific blocker of N-type channels, and nimodipine (1 microM), a specific blocker of L-type Ca(2+) channels, was necessary to inhibit completely the stimulation of TH activity by 55 mM K(+), indicating that Ca(2+) influx through both types of channels contributes to enzyme activation. In contrast, K(+) stimulation of TH activity in nerve fibers and terminals in the iris could be inhibited completely by omega-conotoxin GVIA alone and was unaffected by nimodipine as previously shown. K(+) stimulation of NE release from both ganglia and irises was also blocked completely when omega-conotoxin GVIA was included in the medium, while nimodipine had no significant effect in either tissue. These results indicate that particular cellular processes in specific areas of a neuron are differentially dependent on Ca(2+) influx through N- and L-type Ca(2+) channels.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, Massachusetts 02115, USA.
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Rittenhouse
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Zigmond
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D005136:Eye Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D015640:Ion Channel Gating; D017136:Ion Transport / Q000187:drug effects; D007498:Iris / Q000187:drug effects / Q000294:innervation; D008297:Male; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009553:Nimodipine / Q000494:pharmacology; D009638:Norepinephrine / Q000096:biosynthesis / Q000378:metabolism*; D011188:Potassium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017783:Superior Cervical Ganglion / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D005136:Eye Proteins; D009419:Nerve Tissue Proteins; C053157:omega-conotoxin receptor; D009553:Nimodipine; D020866:omega-Conotoxin GVIA; D014446:Tyrosine 3-Monooxygenase; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine