Regulation of Tyrosine Hydroxylase mRNA Stability by Oxygen in PC12 Cells

Abstract

Mammals evolved to live in the environment that contains 21% of oxygen. In order to preserve optimal tension of oxygen (pO₂) in the blood, organisms developed specialized cells that are O₂-sensors and initiate adaptive and protective regulatory mechanisms during limited availability of oxygen in the environment (i.e. hypoxia). The best known of these O₂-sensitive cells are the carotid body type I glomus cells that immediately detect even relatively moderate reduction in pO₂ in the arterial blood and communicate this information via carotid sinus nerve to the central nervous system networks that regulate the respiratory and cardiovascular systems. A major neurotransmitter that is released during hypoxia from type I cells is catecholamine dopamine. In type I cells hypoxia stimulates the activity of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis (Gonzalez et al, 1977; Hanbauer et al, 1977), and induces dopamine synthesis and release (Fidone et al, 1982a,b; Fishman et al, 1985). Moreover, hypoxia causes a five-fold increase in TH mRNA in a mechanism that is intrinsic to the type I cells, i.e. independent from neural or hormonal inputs (Czyzyk-Krzeska et al, 1992). Further identification and characterization of the O₂-dependent mechanisms that regulate TH gene expression required analysis at the molecular level. This type of studies has been, however, hindered by paucity of tissue provided by carotid body (only approximately 10,000 oxygen sensitive cells per carotid body in the rat). Our laboratory has recently reported that a clonal cell line derived from adrenal medulla tumor -pheochromocytoma- (PC12 cells) demonstrates several characteristics very similar to the carotid body type I cells. During hypoxia PC12 cells depolarize and release dopamine (Zhu et aI, 1996).