MAP kinase-dependent induction of clock gene expression by α₁-adrenergic receptor activation

While peripheral oscillators can be reset by humoral factors such as glucocorticoid hormones, indirect neural communications involving sympathetic and parasympathetic neurons from the suprachiasmatic nucleus to various peripheral tissues suggest that autonomic nerve innervations also function in the resetting and synchronization of peripheral tissues. To study the role of sympathetic adrenergic signaling on clock gene expression, we constructed NIH3T3 cells that stably expressed each of three α₁-adrenergic receptor subtypes (α_1A, α_1B and α_1D). We found that noradrenaline transiently induced the expression of mPer1, mPer2, and mE4bp4 1-2 h after α₁-receptor activation. The extent and time course of clock gene mRNA induction by noradrenaline or the α₁-receptor agonist phenylephrine (PE) was similar to that seen by 50% horse serum shock. Clock gene mRNA induction by PE was inhibited by U0126, a MEK inhibitor, suggesting involvement of the mitogen-activated protein kinase signaling pathway. We also found that both mPer1 and mPer2 mRNAs were induced in the mouse liver 60 min after PE injection. These results suggest that although humoral factors are important for entrainment of the peripheral clock, the autonomic nervous system may also be involved in the process.