Activity-dependent neuronal gene expression is thought to require activation of L-type calcium channels, a view based primarily on studies in which chronic potassium (K ϩ ) depolarization was used to mimic neuronal activity. However, N-type calcium channels are primarily inactivated during chronic depolarization, 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 ϩ , produced a large increase in the percentage of neurons that express tyrosine hydroxylase (TH) mRNA and protein. However, blockade of L-type channels, which completely inhibited K ϩ -induced expression, had no effect on TH expression induced by patterned stimulation. Conversely, blockade of N-type channels completely inhibited TH induction by patterned stimulation, whereas K ϩ -induced expression was unaffected. Similar results were obtained for depolarizationinduced expression of the immediate early genes Nurr1 and Nur77. In addition, TH induction by patterned stimulation was significantly reduced by inhibitors of PKA and PKC but was unaffected by inhibition of the mitogen-activated protein kinase (MAPK) pathway. On the other hand, K ϩ -induced TH expression was significantly reduced by inhibition of the MAPK pathway but was unaffected by inhibitors of PKA or PKC. These results demonstrate that N-type calcium channels can directly link phasic membrane depolarization to gene expression, challenging the view that activation of L-type channels is required for nuclear responses to physiological patterns of activity. Moreover, our data show that phasic and chronic depolarizing stimuli act through distinct mechanisms to induce neuronal gene expression.

Abraham Flexner persuaded the medical establishment of his time that teaching the sciences, from basic to clinical, should be a critical component of the medical student curriculum, thus giving rise to the "preclinical curriculum." However, students' retention of basic science material after the preclinical years is generally poor. The authors believe that revisiting the basic sciences in the fourth year can enhance understanding of clinical medicine and further students' understanding of how the two fields integrate. With this in mind, a return to the basic sciences during the fourth year of medical school may be highly beneficial. The purpose of this article is to (1) discuss efforts to integrate basic science into the clinical years of medical student education throughout the United States and Canada, and (2) describe the highly developed fourth-year basic science integration program at the University of Pittsburgh School of Medicine. In their critical review of medical school curricula of 126 U.S. and 17 Canadian medical schools, the authors found that only 19% of U.S. medical schools and 24% of Canadian medical schools require basic science courses or experiences during the clinical years, a minor increase compared with 1985. Curricular methods ranged from simple lectures to integrated case studies with hands-on laboratory experience. The authors hope to advance the national discussion about the need to more fully integrate basic science teaching throughout all four years of the medical student curriculum by placing a curricular innovation in the context of similar efforts by other U.S. and Canadian medical schools.