Modulation of Ca2+/Calmodulin-Dependent Protein Kinase II Activity by Acute and Chronic Morphine Administration in Rat Hippocampus: Differential Regulation of α and β Isoforms

Calcium/calmodulin-dependent protein kinase II (CaMK II) has been shown to be involved in the regulation of opioid receptor signaling. The present study showed that acute morphine treatment significantly increased both Ca2+/calmodulin-independent and Ca2+/calmodulin-dependent activities of CaMK II in the rat hippocampus, with little alteration in the protein level of either α or β isoform of CaMK II. However, chronic morphine treatment, by which rats were observed to develop apparent tolerance to morphine, significantly down-regulated both Ca2+/calmodulin-independent and Ca2+/calmodulin-dependent activities of CaMK II and differentially regulated the expression of α and β isoforms of CaMK II at protein and mRNA levels. Application of naloxone or discontinuation of morphine treatment after chronic morphine administration, which induced the withdrawal syndrome of morphine, resulted in the overshoot of CaMK II (at both protein and mRNA levels) and its kinase activity. The phenomena of overshoot were mainly observed in the β isoform of CaMK II but not in the α isoform. The effects of both acute and chronic morphine treatments on CaMK II could be completely abolished by the concomitant application of naloxone, indicating that the effects of morphine were achieved through activation of opioid receptors. Our data demonstrated that both acute and chronic morphine treatments could effectively modulate the activity and the expression of CaMK II in the hippocampus.

[1]  G. Aghajanian,et al.  Molecular and cellular basis of addiction. , 1997, Science.

[2]  Howard Eichenbaum,et al.  Abnormal hippocampal spatial representation in aCaMKIIT286A and CREBaD-mice , 1998 .

[3]  Lei Yu,et al.  Protein kinase modulation of mu opioid receptor signalling. , 1996, Cellular signalling.

[4]  T. Kroslak,et al.  Site Mutation in the Rat μ‐Opioid Receptor Demonstrates the Involvement of Calcium/Calmodulin‐Dependent Protein Kinase II in Agonist‐Mediated Desensitization , 1997, Journal of neurochemistry.

[5]  E. Kandel,et al.  Control of Memory Formation Through Regulated Expression of a CaMKII Transgene , 1996, Science.

[6]  H. Schulman,et al.  The multifunctional Ca2+/calmodulin-dependent protein kinases. , 1993, Current opinion in cell biology.

[7]  P. De Koninck,et al.  Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. , 1998, Science.

[8]  E. Smeraldi,et al.  Presynaptic Ca2+/calmodulin-dependent protein kinase II: autophosphorylation and activity increase in the hippocampus after long-term blockade of serotonin reuptake. , 1995, Molecular pharmacology.

[9]  H. Schulman,et al.  Neuronal Ca2+/calmodulin-dependent protein kinases. , 1992, Annual review of biochemistry.

[10]  P. Greengard,et al.  Autophosphorylation and activation of Ca2+/calmodulin-dependent protein kinase II in intact nerve terminals. , 1988, The Journal of biological chemistry.

[11]  G. Pei,et al.  Modulation by calcium/calmodulin-dependent protein kinase II of functional response of delta opioid receptor in neuroblastoma x glioma hybrid (NG108-15) cells , 1997, Neuropharmacology.

[12]  H. Schulman,et al.  Activation of multifunctional Ca2+/calmodulin-dependent kinase in intact hippocampal slices , 1991, Neuron.

[13]  S. Shenolikar,et al.  Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. , 1998, Science.

[14]  H. Schulman,et al.  The multifunctional calcium/calmodulin-dependent protein kinase: from form to function. , 1995, Annual review of physiology.

[15]  E. Nestler.  Molecular mechanisms of opiate and cocaine addiction , 1997, Current Opinion in Neurobiology.

[16]  H. Collier,et al.  Cellular site of opiate dependence , 1980, Nature.

[17]  E. Nestler,et al.  Drug addiction: A model for the molecular basis of neural plasticity , 1993, Neuron.

[18]  M. King,et al.  The role of autophosphorylation in activation of the type II calmodulin-dependent protein kinase. , 1988, The Journal of biological chemistry.

[19]  Michael G. Rosenfeld,et al.  Expression of a multifunctional Ca2+/calmodulin-dependent protein kinase and mutational analysis of its autoregulation , 1989, Neuron.

[20]  R. Wenham,et al.  Glucose activates the multifunctional Ca2+/calmodulin-dependent protein kinase II in isolated rat pancreatic islets. , 1994, The Journal of biological chemistry.

[21]  Y. Lamour,et al.  Brain-derived Neurotrophic Factor Increases Ca2+/Calmodulin-dependent Protein Kinase 2 Activity in Hippocampus* , 1997, The Journal of Biological Chemistry.

[22]  A. Zimprich,et al.  Transfected rat µ opioid receptors (rMOR1 and rMOR1B) stimulate phospholipase C and Ca2+ mobilization , 1995, Neuroreport.

[23]  H. Schulman,et al.  The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  Zhi-jie Cheng,et al.  Functional expression, activation and desensitization of opioid receptor‐like receptor ORL1 in neuroblastoma×glioma NG108‐15 hybrid cells , 1997, FEBS letters.

[25]  Alcino J. Silva,et al.  Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. , 1998, Science.

[26]  Z. Vogel,et al.  Adenylylcyclase Supersensitization in μ-Opioid Receptor-transfected Chinese Hamster Ovary Cells Following Chronic Opioid Treatment (*) , 1995, The Journal of Biological Chemistry.

[27]  Z. Vogel,et al.  Chronic Opioid Treatment Induces Adenylyl Cyclase V Superactivation , 1996, The Journal of Biological Chemistry.