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The Journal of Neuroscience, April 15, 2002, 22(8):3100-3107
A Role for Phosphorylation in the Maintenance of Resurgent Sodium Current in Cerebellar Purkinje Neurons
Tina M. Grieco1, Fatemeh S. Afshari2, and Indira M. Raman1, 2, 3 1 Northwestern University Institute for Neuroscience, 2 Integrated Science Program, and 3 Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208
Cerebellar Purkinje neurons express voltage-gated, tetrodotoxin (TTX)-sensitive sodium channels that not only open and inactivate rapidly during depolarization but also reopen during repolarization, carrying an unusual "resurgent" sodium current. Expression of NaV1.6
subunits appears necessary but not sufficient to generate this component of current; Purkinje cells without NaV1.6 lack resurgent current, but resurgent current is absent from many other NaV1.6-expressing neurons. These observations raise the question of how modulation or modification of the NaV1.6 subunit may lead to production of resurgent current. Previous studies have suggested that sodium channels of Purkinje neurons are subject to a rapid, voltage-dependent, open channel block by an endogenous particle whose unbinding allows resurgent current to flow. To investigate the nature of this block, we recorded TTX-sensitive sodium currents in outside-out patches from Purkinje cells acutely isolated from mice. In all patches, step depolarizations evoked transient current, and step repolarizations evoked resurgent current. The amplitudes of the transient and resurgent currents were highly correlated across patches (R2 > 0.99), suggesting that the blocking agent is closely associated with the channel. Intracellular protease eliminated fast inactivation, indicating that the blocking element, like the fast inactivation gate, may be proteinaceous. Intracellular application of alkaline phosphatase abolished resurgent current and significantly slowed inactivation of transient current. The phosphatase inhibitor vanadate reduced these effects. Together, the results suggest that constitutive phosphorylation of the sodium channel complex of Purkinje neurons is necessary to maintain a functional blocking element and produce resurgent sodium current.
Key words: NaV1.6; med; open channel block; inactivation; phosphorylation; alkaline phosphatase; cerebellum
Copyright © 2002 Society for Neuroscience 0270-6474/02/2283100-08$05.00/0
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