title: Dopaminergic denervation switches dopamine D3 receptor signaling and disrupts its Ca(2+) dependent modulation by CaMKII and calmodulin in striatonigral projections of the rat.
abstract: In striatonigral projections activation of dopamine D3 receptors (D3Rs) potentiates the stimulation of GABA release and cAMP production caused by activation of dopamine D1 receptors (D1Rs). Cytoplasmic [Ca(2+)] in the terminals controls this response by modulating CaMKII, an enzyme that depresses D3R action. To examine the effects of dopamine deprivation on D3R signaling we investigated their function in striatonigral terminals of hemiparkinsonian rats. Denervation switched the signaling cascade initiated by D3R activation. In the non-lesioned side activation of D3R potentiated the stimulatory effects of D1R activation on cAMP production and K(+)-depolarization induced [(3)H] GABA release. In contrast, in the denervated side the stimulatory effects of both D1R activation and forskolin administration were blocked by D3R activation. In non-lesioned slices, D3R responses were inhibited by the activation of CaMKII produced by K(+)-depolarization (via increased Ca(2+) entry). The CaMKII-induced inhibition was blocked by the selective inhibitor KN-62. In denervated tissues the response to D3R stimulation was not modified either by K(+) depolarization or by blocking CaMKII with KN-62. Immunoblotting studies showed that depolarization-induced CaMKII binding to the D3 receptor and CaMKII phosphorylation were suppressed in denervated tissues. We also determined calmodulin expression with PCR and immunoblot techniques. Both techniques showed that calmodulin expression was depressed in the lesioned side. In sum, our studies show that dopaminergic denervation switches the D3R signaling cascade and depresses CaMKII signaling through a process that appears to involve reduced calmodulin levels. Since calmodulin is a major cytoplasmic Ca(2+) buffer our findings suggest that abnormal Ca(2+) buffering may be an important component of the abnormalities observed during dopaminergic denervation.
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico.
authors.forename: Arturo
authors.initials: A
authors.lastname: Avalos-Fuentes
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico.
authors.forename: Sacnité
authors.initials: S
authors.lastname: Albarrán-Bravo
authors.affiliation: Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico.
authors.forename: Santiago
authors.initials: S
authors.lastname: Loya-Lopéz
authors.affiliation: Laboratory of Genomic Medicine, Department of Genetics, National Rehabilitation Institute, Mexico City, Mexico.
authors.forename: Hernán
authors.initials: H
authors.lastname: Cortés
authors.affiliation: Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma del Estado de México, Mexico.
authors.forename: Sergio
authors.initials: S
authors.lastname: Recillas-Morales
authors.affiliation: Laboratory of Genomic Medicine, Department of Genetics, National Rehabilitation Institute, Mexico City, Mexico.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Magaña
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico.
authors.forename: Francisco
authors.initials: F
authors.lastname: Paz-Bermúdez
authors.affiliation: Neurosciences Program Bloomington Indiana University Bloomington, IN, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rangel-Barajas
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Aceves
authors.affiliation: Department of Physiology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: David
authors.initials: D
authors.lastname: Erlij
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico. Electronic address: bfloran@fisio.cinvestav.mx.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Florán
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008474:Medial Forebrain Bundle / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine; D010766:Phosphorylation / Q000187:drug effects; D017208:Rats, Wistar; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D015398:Signal Transduction; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002147:Calmodulin; D015226:Dinucleoside Phosphates; C493595:Drd3 protein, rat; D050637:Receptors, Dopamine D3; C013797:adenylyl cytidine; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; D000242:Cyclic AMP; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium; D004298:Dopamine