Dopamine receptor-mediated Ca(2+) signaling in striatal medium spiny neurons.
Inositol 1,4,5-trisphosphate (InsP(3)) and cAMP are the two second messengers that play an important role in neuronal signaling. Here, we investigated the interactions of InsP(3)- and cAMP-mediated signaling pathways activated by dopamine in striatal medium spiny neurons (MSN). We found that in approximately 40% of the MSN, application of dopamine elicited robust repetitive Ca(2+) transients (oscillations). In pharmacological experiments with specific agonists and antagonists, we found that the observed Ca(2+) oscillations were triggered by activation of D1 class dopamine receptors (DARs). We further demonstrated that activation of phospholipase C was required for induction of dopamine-induced Ca(2+) oscillations and that maintenance of dopamine-evoked Ca(2+) oscillations required both Ca(2+) influx and Ca(2+) mobilization from internal Ca(2+) stores. In "priming" experiments with a type 2 5-hydroxytryptamine receptor agonist, we have shown a likely role for calcyon in coupling D1 class DARs with Ca(2+) oscillations in MSN. In experiments with the DAR-specific agonist SKF83959, we discovered that phospholipase C activation alone could not account for dopamine-induced Ca(2+) oscillations. We further demonstrated that direct activation of protein kinase A by 8-bromo-cAMP or inhibition of protein phosphatase-1 (PP1) or calcineurin (PP2B) resulted in elevation of basal Ca(2+) levels in MSN, but not in Ca(2+) oscillations. In experiments with competitive peptides, we have shown an importance of type 1 InsP(3) receptor association with PP1alpha and with AKAP9.protein kinase A for dopamine-induced Ca(2+) oscillations. In experiments with MSN from DARPP-32 knock-out mice, we demonstrated a regulatory role of DARPP-32 in dopamine-induced Ca(2+) oscillations. Our results indicate that, following D1 class DAR activation, InsP(3) and cAMP signaling pathways converge on the type 1 InsP(3) receptor, resulting in Ca(2+) oscillations in MSN.
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, USA.
Tie-Shan
TS
Tang
Ilya
I
Bezprozvanny
D000818:Animals; D001479:Basal Ganglia / Q000166:cytology*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D020239:Receptor Cross-Talk; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D015290:Second Messenger Systems
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D017447:Receptors, Dopamine D1; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP