Type II cAMP-dependent Protein Kinase-deficientDrosophila Are Viable but Show Developmental, Circadian, and Drug Response Phenotypes*

We identified a unique type II cAMP-dependent protein kinase regulatory subunit (PKA-RII) gene in Drosophila melanogaster and a severely hypomorphic if not null mutation, pka-RII EP(2)2162 . Extracts from pka- RII EP(2)2162 flies selectively lack RII-specific autophosphorylation activity and show significantly reduced cAMP binding activity, attributable to the loss of functional PKA-RII. pka-RII EP(2)2162 shows 2-fold increased basal PKA activity and ∼40% of normal cAMP-inducible PKA activity.pka-RII EP(2)2162 is fully viable but displays abnormalities of ovarian development and multiple behavioral phenotypes including arrhythmic circadian locomotor activity, decreased sensitivity to ethanol and cocaine, and a lack of sensitization to repeated cocaine exposures. These findings implicate type II PKA activity in these processes in Drosophila and imply a common role for PKA signaling in regulating responsiveness to cocaine and alcohol.

[1]  J. Hirsh,et al.  Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster , 2000, Current Biology.

[2]  E R Kandel,et al.  Genetic approaches to memory storage. , 1999, Trends in genetics : TIG.

[3]  R. Hardie,et al.  Modulation of the Light Response by cAMP inDrosophila Photoreceptors , 1999, The Journal of Neuroscience.

[4]  J. Hirsh,et al.  Requirement of circadian genes for cocaine sensitization in Drosophila. , 1999, Science.

[5]  W. Catterall,et al.  Voltage-Dependent Neuromodulation of Na+ Channels by D1-Like Dopamine Receptors in Rat Hippocampal Neurons , 1999, The Journal of Neuroscience.

[6]  M. Colledge,et al.  AKAPs: from structure to function. , 1999, Trends in cell biology.

[7]  E. Pothos,et al.  D2-Like Dopamine Autoreceptor Activation Reduces Quantal Size in PC12 Cells , 1998, The Journal of Neuroscience.

[8]  T. Tully,et al.  Ethanol Intoxication in Drosophila: Genetic and Pharmacological Evidence for Regulation by the cAMP Signaling Pathway , 1998, Cell.

[9]  J. Wehner,et al.  Defective Motor Behavior and Neural Gene Expression in RIIβ-Protein Kinase A Mutant Mice , 1998, The Journal of Neuroscience.

[10]  R. Wightman,et al.  Profound neuronal plasticity in response to inactivation of the dopamine transporter. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Aaron DiAntonio,et al.  Postsynaptic PKA Controls Quantal Size and Reveals a Retrograde Signal that Regulates Presynaptic Transmitter Release in Drosophila , 1998, Neuron.

[12]  Jay Hirsh,et al.  Stereotypic behavioral responses to free-base cocaine and the development of behavioral sensitization in Drosophila , 1998, Current Biology.

[13]  T. Tully,et al.  Defective Learning in Mutants of the Drosophila Gene for a Regulatory Subunit of cAMP-Dependent Protein Kinase , 1997, The Journal of Neuroscience.

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

[15]  R. Christopher Pierce,et al.  A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants , 1997, Brain Research Reviews.

[16]  A. L. Goldin,et al.  Dopaminergic Modulation of Sodium Current in Hippocampal Neurons via cAMP-Dependent Phosphorylation of Specific Sites in the Sodium Channel α Subunit , 1997, The Journal of Neuroscience.

[17]  D. Kalderon,et al.  Drosophila melanogaster deficient in protein kinase A manifests behavior-specific arrhythmia but normal clock function , 1997, Molecular and cellular biology.

[18]  J. Scott,et al.  Type II regulatory subunits are not required for the anchoring-dependent modulation of Ca2+ channel activity by cAMP-dependent protein kinase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  S. M. Jackson,et al.  cut interacts with Notch and protein kinase A to regulate egg chamber formation and to maintain germline cyst integrity during Drosophila oogenesis. , 1997, Development.

[20]  U. Müller.  Neuronal cAMP-dependent protein kinase type II is concentrated in mushroom bodies of Drosophila melanogaster and the honeybee Apis mellifera. , 1997, Journal of neurobiology.

[21]  T. Yoshioka,et al.  Purification of a regulatory subunit of type II cAMP-dependent protein kinase from Drosophila heads. , 1997, Biochemical and biophysical research communications.

[22]  R. Idzerda,et al.  Compensatory Regulation of RIα Protein Levels in Protein Kinase A Mutant Mice* , 1997, The Journal of Biological Chemistry.

[23]  Tim Tully,et al.  Associative Learning Disrupted by Impaired Gs Signaling in Drosophila Mushroom Bodies , 1996, Science.

[24]  P. Rørth,et al.  A modular misexpression screen in Drosophila detecting tissue-specific phenotypes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[25]  N. Perrimon.  Serpentine Proteins Slither into the Wingless and Hedgehog Fields , 1996, Cell.

[26]  P. Kalivas,et al.  Repeated intra-ventral tegmental area administration of SKF-38393 induces behavioral and neurochemical sensitization to a subsequent cocaine challenge. , 1996, The Journal of pharmacology and experimental therapeutics.

[27]  R. Todd,et al.  Inhibition of dopamine synthesis by dopamine D2 and D3 but not D4 receptors. , 1996, The Journal of pharmacology and experimental therapeutics.

[28]  P. Ingham,et al.  hedgehog is required for the proliferation and specification of ovarian somatic cells prior to egg chamber formation in Drosophila. , 1996, Development.

[29]  A. Mccarthy.  Development , 1996, Current Opinion in Neurobiology.

[30]  R. Hammer.  The Neurobiology of Cocaine: Cellular and Molecular Mechanisms , 1995 .

[31]  D. Kalderon,et al.  Localization and functions of Protein Kinase A during Drosophila oogenesis , 1995, Mechanisms of Development.

[32]  W. Quinn,et al.  Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila , 1994, Cell.

[33]  F. Jackson,et al.  Altered circadian pacemaker functions and cyclic AMP rhythms in the drosophila learning mutant dunce , 1994, Neuron.

[34]  D. Kalderon,et al.  Genetic investigation of cAMP-dependent protein kinase function in Drosophila development. , 1993, Genes & development.

[35]  M. Muskavitch,et al.  Complex function and expression of Delta during Drosophila oogenesis. , 1993, Genetics.

[36]  I. Carré,et al.  Oscillator control of cell division in Euglena: cyclic AMP oscillations mediate the phasing of the cell division cycle by the circadian clock. , 1993, Journal of cell science.

[37]  A. Mahowald,et al.  The neurogenic locus brainiac cooperates with the Drosophila EGF receptor to establish the ovarian follicle and to determine its dorsal-ventral polarity. , 1992, Development.

[38]  S. Artavanis-Tsakonas,et al.  The involvement of the Notch locus in Drosophila oogenesis. , 1992, Development.

[39]  I. Carré,et al.  cAMP-dependent kinases in the algal flagellate Euglena gracilis. , 1992, The Journal of biological chemistry.

[40]  Y. Jan,et al.  Role of neurogenic genes in establishment of follicle cell fate and oocyte polarity during oogenesis in Drosophila , 1991, Cell.

[41]  E. Nestler,et al.  A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function , 1991, Brain Research.

[42]  J. Scott.  Cyclic nucleotide-dependent protein kinases. , 1991, Pharmacology & therapeutics.

[43]  Susan S. Taylor,et al.  cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. , 1990, Annual review of biochemistry.

[44]  J. Takahashi,et al.  Twenty-four hour oscillation of cAMP in chick pineal cells: Role of cAMP in the acute and circadian regulation of melatonin production , 1989, Neuron.

[45]  G. McKnight,et al.  Distinct patterns of cAMP-dependent protein kinase gene expression in mouse brain , 1989, Neuron.

[46]  G. Rubin,et al.  Isolation and characterization of Drosophila cAMP-dependent protein kinase genes. , 1988, Genes & development.

[47]  J. H. Schwartz,et al.  Molecular mechanisms for memory: second-messenger induced modifications of protein kinases in nerve cells. , 1987, Annual review of neuroscience.

[48]  O. Rosen,et al.  Drosophila cAMP-dependent protein kinase. , 1984, The Journal of biological chemistry.

[49]  J. Takahashi,et al.  Adenylate cyclase activation shifts the phase of a circadian pacemaker. , 1983, Science.

[50]  E. Krebs,et al.  Primary structure of the regulatory subunit of type II cAMP-dependent protein kinase from bovine cardiac muscle. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[51]  D. McAdoo,et al.  Mechanism for shifting the phase of a circadian rhythm by serotonin: involvement of cAMP. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[52]  B. Bainbridge,et al.  Genetics , 1981, Experientia.

[53]  O. Rosen,et al.  Mechanism of self-phosphorylation of adenosine 3':5'-monophosphate-dependent protein kinase from bovine cardiac muscle. , 1976, The Journal of biological chemistry.

[54]  J. Erlichman,et al.  Reversible autophosphorylation of a cyclic 3':5'-AMP-dependent protein kinase from bovine cardiac muscle. , 1975, The Journal of biological chemistry.

[55]  Y. Nishizuka,et al.  Multiplicity of adenosine 3',5'-monophosphate-dependent protein kinases from rat liver and mode of action of nucleoside 3',5'-monophosphate. , 1972, The Journal of biological chemistry.

[56]  P. Greengard,et al.  Cyclic nucleotide-dependent protein kinases. IV. Widespread occurrence of adenosine 3',5'-monophosphate-dependent protein kinase in various tissues and phyla of the animal kingdom. , 1969, Proceedings of the National Academy of Sciences of the United States of America.