Received for publication July 7, 2005.
Revised November 29, 2005.
Accepted for publication November 29, 2005.

Involvement of cAMP/cAMP-Dependent Protein Kinase Signaling Pathway in Regulation of Na⁺,K⁺-ATPase upon Activation of Opioid Receptors by Morphine

Abstract

The depolarization of neurons induced by impairment of Na⁺,K⁺-ATPase activity after chronic opiate treatment has been shown to involve the development of opioid dependence. However, the mechanisms underlying changes in Na⁺,K⁺-ATPase activity following opioid treatment are unclear. The best-established molecular adaptation to chronic opioid exposure is up-regulation of the cAMP/PKA signaling pathway, this study, therefore, was undertaken to investigate the role of up-regulation of cAMP/PKA signaling pathway in alteration of the mouse hippocampal Na⁺,K⁺-ATPase activity. The results demonstrated that acute morphine treatment dose-dependently stimulated Na⁺,K⁺-ATPase activity. This action could be significantly suppressed by adenylyl cyclase activator, forskolin or the cAMP analogue, db-cAMP. Contrary to acute morphine treatment, chronic morphine treatment significantly inhibited Na⁺,K⁺-ATPase activity. Moreover, an additional decrease in Na⁺,K⁺-ATPase activity was observed by naloxone precipitation. The effects of both acute and chronic morphine treatment on Na⁺,K⁺-ATPase activity were naltrexone-reversible. The regulation of Na⁺,K⁺-ATPase activity by morphine was inversely correlated with intracellular cAMP accumulation. H-89, a specific PKA inhibitor, mimicked the stimulatory effect of acute morphine but antagonized the inhibitory effect of chronic morphine on Na⁺,K⁺-ATPase activity. However, okadaic acid, a protein phosphatase inhibitor, suppressed acute morphine stimulation but potentiated chronic morphine inhibition of Na⁺,K⁺-ATPase activity. The regulation of Na⁺,K⁺-ATPase activity by morphine treatment appeared to associate with the alteration in phosphorylation level, but not to be relevant to the change in abundance of of Na⁺,K⁺-ATPase. These findings strongly demonstrate that cAMP/PKA signaling pathway involves in regulation of Na⁺,K⁺-ATPase activity after activation of opioid receptors.

Key words: Opioid, Gi family, Adenylyl cyclases, cAMP, Protein Kinase A, Ion transporters (SERCA, Na/K ATPase, CFTR), Opioids

This article has been cited by other articles:

				Z.-Q. Wu, J. Chen, Z.-Q. Chi, and J.-G. Liu Involvement of Dopamine System in Regulation of Na+,K+-ATPase in the Striatum upon Activation of Opioid Receptors by Morphine Mol. Pharmacol., February 1, 2007; 71(2): 519 - 530. [Abstract] [Full Text] [PDF]