Regulation of RGS proteins by chronic morphine in rat locus coeruleus
Regulation of RGS proteins by chronic morphine in rat locus coeruleus
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DOI：
10.1046/j.1460-9568.2003.02529.x
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发表时间：
2003-03-01
影响因子：
3.4
通讯作者：
Nestler, EJ
中科院分区：
文献类型：
--
作者：
Gold, SJ;Han, MH;Nestler, EJ
The present study explored a possible role for RGS (regulators of G protein signalling) proteins in the long term actions of morphine in the locus coeruleus (LC), a brainstem region implicated in opiate physical dependence and withdrawal. Morphine influences LC neurons through activation of mu-opioid receptors, which, being Gi/o-linked, would be expected to be modulated by RGS proteins. We focused on several RGS subtypes that are known to be expressed in this brain region. Levels of mRNAs encoding RGS2, -3, -4, -5, -7, -8 and -11 are unchanged following chronic morphine, but RGS2 and -4 mRNA levels are increased 2-3-fold 6 h following precipitation of opiate withdrawal. The increases in RGS2 and -4 mRNA peak after 6 h of withdrawal and return to control levels by 24 h. Immunoblot analysis of RGS4 revealed a striking divergence between mRNA and protein responses in LC: protein levels are elevated twofold following chronic morphine and decrease to control values by 6 h of withdrawal. In contrast, levels of RGS7 and -11 proteins, the only other subtypes for which antibodies are available, were not altered by these treatments. Intracellular application of wild-type RGS4, but not a GTPase accelerating-deficient mutant of RGS4, into LC neurons diminished electrophysiological responses to morphine. The observed subtype- and time-specific regulation of RGS4 protein and mRNA, and the diminished morphine-induced currents in the presence of elevated RGS4 protein levels, indicate that morphine induction of RGS4 could contribute to aspects of opiate tolerance and dependence displayed by LC neurons.
