Differing temporal roles of Ca21 and cAMP in nicotine-elicited elevation of tyrosine hydroxylase mRNA

Gueorguiev, Volodia D., Richard J. Zeman, Bhargava Hiremagalur, Ana Menezes, and Esther L. Sabban. Differing temporal roles of Ca21 and cAMP in nicotine-elicited elevation of tyrosine hydroxylase mRNA. Am. J. Physiol. 276 (Cell Physiol. 45): C54–C65, 1999.—The involvement of cAMPand Ca21-mediated pathways in the activation of tyrosine hydroxylase (TH) gene expression by nicotine was examined in PC-12 cells. Extracellular Ca21 and elevations in intracellular Ca21 concentration ([Ca]i) were required for nicotine to increase TH mRNA. The nicotine-elicited rapid rise in [Ca]i was inhibited by blockers of either L-type or N-type, and to a lesser extent P/Q-, but not T-type, voltage-gated Ca21 channels. With continual nicotine treatment, [Ca]i returned to basal levels within 3–4 min. After a lag of ,5–10 min, there was a smaller elevation in [Ca]i that persisted for 6 h and displayed different responsiveness to Ca21 channel blockers. This second phase of elevated [Ca]i was blocked by an inhibitor of store-operated Ca21 channels, consistent with the observed generation of inositol trisphosphate. 1,2-Bis(2-aminophenoxy)ethane-N,N,N8,N8-tetraacetic acid-AM (BAPTA-AM), when added before or 2 h after nicotine, prevented elevation of TH mRNA. Nicotine treatment significantly raised cAMP levels. Addition of the adenylyl cyclase inhibitor 28,58dideoxyadenosine (DDA) prevented the nicotine-elicited phosphorylation of cAMP response element binding protein. DDA also blocked the elevation of TH mRNA only when added after the initial transient rise in [Ca]i and not after 1 h. This study reveals that several temporal phases are involved in the induction of TH gene expression by nicotine, each of them with differing requirements for Ca21 and cAMP.