D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade.
In spite of the recognition that striatal D(2) receptors are critical determinants in a variety of psychomotor disorders, the cellular mechanisms by which these receptors shape neuronal activity have remained a mystery. The studies presented here reveal that D(2) receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca(2+) currents through L-type Ca(2+) channels, resulting in diminished excitability. This modulation is mediated by G(beta)(gamma) activation of phospholipase C, mobilization of intracellular Ca(2+) stores, and activation of the calcium-dependent phosphatase calcineurin. In addition to providing a unifying mechanism to explain the apparently divergent effects of D(2) receptors in striatal medium spiny neurons, this novel signaling linkage provides a foundation for understanding how this pivotal receptor shapes striatal excitability and gene expression.
Hernandez-Lopez
S
S
Department of Physiology and Institute for Neuroscience, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Tkatch
T
T
Perez-Garci
E
E
Galarraga
E
E
Bargas
J
J
Hamm
H
H
Surmeier
D J
DJ
D000200:Action Potentials / Q000187:drug effects; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001464:Barium / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D054799:Phospholipase C beta; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013469:Sulpiride / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D065095:Calcineurin Inhibitors; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D017448:Receptors, Dopamine D2; D001464:Barium; D013469:Sulpiride; D015544:Inositol 1,4,5-Trisphosphate; D019703:Calcineurin; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D002118:Calcium; D004298:Dopamine