Involvement of α7 Nicotinic Acetylcholine Receptors in Activation of Tyrosine Hydroxylase and Dopamine β‐Hydroxylase Gene Expression in PC12 Cells

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Abstract
Nicotine treatment increases intracellular free Ca2+ concentration [Ca2+]i, stimulates catecholamine release, and elevates gene expression for the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH). However, the type of nicotinic acetylcholine receptors (nAChRs) mediating these events is unclear. The nAChR receptor antagonists α-bungarotoxin (αBTX) and methyllycaconitine greatly reduced the nicotine-triggered initial transient rise in [Ca2+]i and prevented the second prolonged elevation of [Ca2+]i, suggesting the involvement of α7 nAChRs. Two specific α7 nicotinic agonists, 3-(2,4-dimethoxybenzilidene)anabaseine (DMXB) and E,E-3-(cinnamylidene)anabaseine (3-CA), were found to elicit a small, delayed increase in [Ca2+]i with kinetics and magnitude similar to the second elevation observed with nicotine. This increase was inhibited by the inositol trisphosphate receptor antagonist xestospongin C. Exposure to 3-CA or DMXB for 6 or 24 h elevated TH and DBH mRNA levels two- to fourfold over control levels. These agonists were more effective than nicotine alone in increasing TH and DBH gene expression and significantly elevated [Ca2+]i for up to 6 h. The increase in [Ca2+]i or the elevation in TH mRNA by 3-CA was completely inhibited by αBTX. This study, for the first time, implicates stimulation of α7 nAChRs in the activation of TH and DBH gene expression.