Most forms of repeated or chronic stress induce tyrosine hydroxylase (TH) in adrenal medulla, sympathetic ganglia and locus coeruleus, and some types of stress induce TH in midbrain dopamine neuron1-4
. Current hypotheses describing the molecular and signaling mechanisms responsible for this response focus primarily on transcriptional regulation and are based primarily on results of studies performed in vivo
using adrenal medulla or in cultured PC12 and neuroblastoma cells. According to these models, stress leads to increased firing of afferent nerve fibers, like the splanchnic nerve for the adrenal medulla, resulting in enhanced activation of multiple plasma membrane receptors on postsynaptic catecholaminergic cell bodies by neurotransmitters released from these afferents. This receptor activation causes stimulation of multiple signaling pathways, leading to activation and/or induction of transcription factors that stimulate the TH gene promoter. The resulting increase in TH gene transcription rate leads to induction of TH mRNA. The consequent increase in TH protein is presumably responsible for maintaining the appropriate levels of catecholamine neurotransmitters during periods of sustained catecholamine release, which occur during chronic or repeated stress.
This model is supported by a large amount of evidence. TH mRNA is induced by almost all stressors and this induction precedes the increases in TH protein 1-4
. Using a number of technically-difficult assays, including nuclear run-on assays, measurement of changes in the levels of nuclear RNA primary transcripts, and measurement of changes in expression of reporter genes driven by the TH gene promoter in transgenic mice, a number of laboratories have shown that TH gene transcription rate increases in response to stress and other stimuli in both adrenal medulla and locus coeruleus. Finally, stress leads to expected changes in transcription factors that are known to regulate the TH gene promoter 5-11
. Interestingly, in the adrenal medulla, the time course of this transcriptional response is dependent on the duration of the stress. Short-term stress leads to rapid, but transient transcriptional activation, whereas chronic or repeated stress is associated with sustained stimulation of the TH gene 5-14
. This sustained stimulation is apparently mediated by different transcription factors than those that regulate the gene during short-term stress and results in long-term induction of TH mRNA and TH protein.
Even though this model is consistent with much of the available evidence, there are a number of important discrepancies that do not fit well. (1) The observed effect of a particular stressor on TH expression differs depending on the tissue being studied 2, 15, 16
. For instance, the responses observed in the adrenal medulla are not always identical to those observed in brain regions. (2) Increases in TH mRNA levels do not always correlate closely with increases in TH gene transcription rate in response to some stressors 8, 9, 17-19
, suggesting that TH mRNA stability is regulated. (3) Induction of TH mRNA does not always lead to induction of TH protein, suggesting that either TH protein synthesis or degradation is regulated by stress 14, 20-24
. In this report, we will briefly discuss some of these discrepancies and relate them to the hypothesis that trans-factors binding to the 3′UTR of TH mRNA may be regulated by stress, resulting in regulation of TH mRNA stability and translation in different catecholaminergic cell types.