Transmitter- and Activity-Dependent Inhibition of Neuronal Firing

+ See all authors and affiliations

Science's STKE  09 Sep 2003:
Vol. 2003, Issue 199, pp. tw346-TW346
DOI: 10.1126/stke.2003.199.tw346

Neuronal excitability depends upon the activation of voltage-gated Na+ channels. Various neuromodulators reduce Na+ channel availability (and thus neuronal excitability) through the activation of heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPCR)-mediated signaling pathways that lead to channel phosphorylation. Carr et al. used a combination of electrophysiological and pharmacological analysis to show that the reduction in Na+ channel availability produced by GPCR activation closely resembled slow inactivation--a slow, voltage-dependent state that occurs in response to prolonged depolarization and during repetitive firing. The authors investigated the kinetics and voltage dependence of changes in Na+ channel availability in mouse prefrontal cortex pyramidal neurons in response to treatment with the 5-HT2a/c (5-hydroxytryptamine) receptor agonist 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). The effects of receptor stimulation were voltage-dependent, and DOI accelerated the development and extent of slow inactivation without affecting the time constant of recovery. Moreover, the effects of DOI, like slow inactivation, were inhibited by increases in the extracellular Na+ concentration. Similarly, direct pharmacological activation of protein kinase A and protein kinase C promoted a slow inactivation-like state. The voltage dependence of phosphorylation-dependent channel inactivation occurred after phosphorylation, and mutational analysis indicated that channel phosphorylation was not required for depolarization-dependent development of slow inactivation. DOI accelerated the elevation of threshold that occurs during sustained firing (when the interspike membrane potential remains somewhat depolarized) and led to early failure of action potential generation. Thus, GPCR stimulation, by promoting a slow inactivation-like state, can selectively modulate sustained neuronal activity to produce a novel form of neuronal plasticity.

D. B. Carr, M. Day, A. R. Cantrell, J. Held, T. Scheuer, W. A. Catterall, D. J. Surmeier, Transmitter modulation of slow, activity-dependent alterations in sodium channel availability endows neurons with a novel form of cellular plasticity. Neuron 39, 793-806 (2003). [Online Journal]

Related Content