Phosphoinositide 3-kinase isoforms selectively couple receptors to vascular L-type Ca(2+) channels.
Heterodimeric class I phosphoinositide 3-kinase (PI3K) has been shown to be involved in the stimulation of voltage-gated Ca(2+) channels by various mediators. In this study, we bring evidences that vascular L-type Ca(2+) channels can be modulated by both tyrosine kinase-regulated class Ia and G protein-regulated class Ib PI3Ks. Purified recombinant PI3Ks increased the peak Ca(2+) channel current density when applied intracellularly. Furthermore, PI3Kalpha-, beta-, and delta-mediated stimulations of Ca(2+) channel currents were increased by preactivation by a phosphotyrosyl peptide, whereas PI3Kgamma- and beta-mediated effects were increased by Gbetagamma. In freshly isolated and cultured vascular myocytes, angiotensin II and Gbetagamma stimulated L-type Ca(2+) channel current. In contrast, platelet-derived growth factor (PDGF)-BB and the phosphotyrosyl peptide did not stimulate Ca(2+) channel current in freshly isolated cells despite the presence of endogenous PDGF receptors and PI3Kalpha and PI3Kgamma. Interestingly, when endogenous PI3Kbeta expression arose in cultured myocytes, both PDGF and phosphotyrosyl peptide stimulated Ca(2+) channels through PI3Kbeta, as revealed by the inhibitory effect of an anti-PI3Kbeta antibody. These results suggest that endogenous PI3Kbeta but not PI3Kalpha is specifically involved in PDGF receptor-induced stimulation of Ca(2+) channels and that different isoforms of PI3K regulate physiological increases of Ca(2+) influx in vascular myocytes stimulated by vasoconstrictor or growth factor.
Macrez
N
N
Laboratoire de Signalisation et Interactions Cellulaires, Université de Bordeaux II, France. nathalie.macrez@umr5017.u-bordeaux2.fr
Mironneau
C
C
Carricaburu
V
V
Quignard
J F
JF
Babich
A
A
Czupalla
C
C
Nürnberg
B
B
Mironneau
J
J
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000378:metabolism / Q000494:pharmacology; D000077214:Becaplermin; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015686:Gene Products, env / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D007478:Iontophoresis; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D014162:Transfection; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D015686:Gene Products, env; D007527:Isoenzymes; D010446:Peptide Fragments; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D014662:Vasoconstrictor Agents; C093834:peptide fragment P828; D000804:Angiotensin II; D000077214:Becaplermin; D001464:Barium; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D020962:Heterotrimeric GTP-Binding Proteins; D002118:Calcium