title: CCK-8-evoked cationic currents in substantia nigra dopaminergic neurons are mediated by InsP3-induced Ca2+ release.
abstract: Our recent study demonstrated that by activating CCK-A receptors, CCK-8 excites substantia nigra (SN) dopaminergic (DA) neurons via increasing a non-selective cationic conductance. In the present study, we further studied the molecular mechanism by which CCK-8 induces cationic currents in SN DA neurons. CCK-8-evoked inward currents were inhibited by the intracellular perfusion of GDP-beta-S (1 mM). In DA neurons internally perfused with GTP-gamma-S (0.5 mM), the inward currents produced by CCK-8 became irreversible. Pretreating DA neurons with 500 ng/ml pertussis toxin (PTX) did not significantly affect the ability of CCK-8 to induce cationic currents. Intracellular application of heparin (2 mg/ml), an inositol 1,4,5-trisphosphate (InsP3) receptor antagonist, and buffering intracellular calcium with the Ca(2+)-chelator BAPTA (10 mM) suppressed CCK-8-evoked cationic currents. Dialyzing DA neurons with protein kinase C (PKC) inhibitors, staurosporine and PKC(19-31), failed to prevent CCK-8 from generating cationic currents. It is concluded that PTX-insensitive G-proteins mediate CCK-8-induced enhancement of cationic conductance of SN DA neurons. The coupling mechanism via G-proteins is likely to involve the generation of InsP3, and subsequent InsP3-evoked Ca2+ release from the intracellular store results in activating the non-selective cationic conductance.
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Taiwan, ROC.
authors.forename: T
authors.initials: T
authors.lastname: Wu
authors.forename: H L
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D037342:Pertussis Toxin; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D012844:Sincalide / Q000494:pharmacology*; D019311:Staurosporine; D013378:Substantia Nigra / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007473:Ion Channels; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D013873:Thionucleotides; D010566:Virulence Factors, Bordetella; D006153:Guanosine Diphosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004533:Egtazic Acid; C023427:guanosine 5'-O-(2-thiodiphosphate); D015544:Inositol 1,4,5-Trisphosphate; D006493:Heparin; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019311:Staurosporine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D012844:Sincalide; D002118:Calcium; D004298:Dopamine