Presynaptic CaMKIIα modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca(2+) dependent manner.
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 Ca(2+) activation of CaMKIIα. In SNr synaptosomes two procedures that increase cytoplasmic Ca(2+), 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 Ca(2) -free solutions or with the selective Ca(2+) 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 [(3)H]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 [(3)H]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 Ca(2+) 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.
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KN-62 dopamine KN-62 Ca(2+) GABA dopamine Ca(2+) Ca(2+) ionomycin K(+) KN-62 cAMP dopamine KN-62 ionomycin K(+) Ca(2) Ca(2+) nifedipine K(+) K(+) K(+) Ca(2+) dopamine CaMKIIα CaMKIIα D3 receptors D3 receptors D1 receptor CaMKIIα D3 D1 [(3)H]GABA D1 and D4 receptor CaMKIIα D3 receptors D3 receptors D1 receptor D3 receptor CaMKIIα D3 and D1 dopamine receptors CaMKIIα D3 receptors KN-62 CaMKIIα CaMKIIα dopamine D3 receptor PD 128,907 SKF 38393 KN-62 dopamine [(3)H]GABA