Physiological patterns of electrical stimulation can induce neuronal gene expression by activating N-type calcium channels

Activity-dependent neuronal gene expression is thought to require activatio n of L-type calcium channels, a view based primarily on studies in which ch ronic potassium (K+) depolarization was used to mimic neuronal activity. Ho wever, N-type calcium channels are primarily inactivated during chronic dep olarization, and their potential contribution to gene expression induced by physiological patterns of stimulation has not been defined. In the present study, electrical stimulation of dissociated primary sensory neurons at 5 Hz, or treatment with elevated K+, produced a large increase in the percent age of neurons that express tyrosine hydroxylase (TH) mRNA and protein. How ever, blockade of L-type channels, which completely inhibited K+-induced ex pression, had no effect on TH expression induced by patterned stimulation. Conversely, blockade of N-type channels completely inhibited TH induction b y patterned stimulation, whereas K+-induced expression was unaffected. Simi lar results were obtained for depolarization-induced expression of the imme diate early genes Nurr1 and Nur77. In addition, TH induction by patterned s timulation was significantly reduced by inhibitors of PKA and PKC but was u naffected by inhibition of the mitogen-activated protein kinase (MAPK) path way. On the other hand, K+-induced TH expression was significantly reduced by inhibition of the MAPK pathway but was unaffected by inhibitors of PKA o r PKC. These results demonstrate that N-type calcium channels can directly link phasic membrane depolarization to gene expression, challenging the vie w that activation of L-type channels is required for nuclear responses to p hysiological patterns of activity. Moreover, our data show that phasic and chronic depolarizing stimuli act through distinct mechanisms to induce neur onal gene expression.