title: Presynaptic CaMKIIα modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca²⁺ dependent manner.
abstract: CaMKIIα is expressed at high density in the nucleus accumbens where it binds to postsynaptic D3 receptors inhibiting their effects. In striatonigral projections, activation of presynaptic D3 receptors potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca²⁺ activation of CaMKIIα. In SNr synaptosomes two procedures that increase cytoplasmic Ca²⁺, ionomycin and K⁺-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective CaMKIIα inhibitor KN-62 reversed the blockade produced by ionomycin and K⁺-depolarization. Incubation in either Ca²-free solutions or with the selective Ca²⁺ blocker nifedipine, also reversed the blocking effects of K⁺-depolarization. Immunoblot studies showed that K⁺-depolarization increased CaMKIIα phosphorylation in a KN-62 sensitive manner and promoted CaMKIIα binding to D3 receptors. In K⁺-depolarized tissues, D3 receptors potentiated D1 receptor-induced stimulation of [³H]GABA release only when CaMKIIα was blocked with KN-62. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED₅₀ for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [³H]GABA release. KN-62 changed ED₅₀ for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, CaMKIIα inhibits the action of D3 receptors in a Ca²⁺ dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects.
authors.affiliation: Department of Pharmacology, CINVESTAV-IPN, Mexico.
authors.forename: Arturo
authors.initials: A
authors.lastname: Avalos-Fuentes
authors.forename: Santiago
authors.initials: S
authors.lastname: Loya-López
authors.forename: Aleida
authors.initials: A
authors.lastname: Flores-Pérez
authors.forename: Sergio
authors.initials: S
authors.lastname: Recillas-Morales
authors.forename: Hernán
authors.initials: H
authors.lastname: Cortés
authors.forename: Francisco
authors.initials: F
authors.lastname: Paz-Bermúdez
authors.forename: Jorge
authors.initials: J
authors.lastname: Aceves
authors.forename: David
authors.initials: D
authors.lastname: Erlij
authors.forename: Benjamín
authors.initials: B
authors.lastname: Florán
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000378:metabolism*; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D018491:Dopamine Agonists; C493595:Drd3 protein, rat; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D000242:Cyclic AMP; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517675:Camk2a protein, rat