title: Chick RGS2L demonstrates concentration-dependent selectivity for pertussis toxin-sensitive and -insensitive pathways that inhibit L-type Ca2+ channels.
abstract: In neuronal cells, the influx of Ca2+ ions through voltage-dependent L-type calcium (L) channels couples excitation to multiple cellular functions. In addition to voltage, several neurotransmitters, hormones and cytokines regulate L channel gating via binding to G-protein-coupled receptors. Intracellular molecules that modify G-protein activity - such as regulator of G-protein-signalling (RGS) proteins - are therefore potential candidates for regulating Ca2+ influx through L channels. Here we show that a novel RGS2 splice variant from chick dorsal root ganglion (DRG) neurons, RGS2L, reduces bradykinin (BK)-mediated inhibition of neuronal L channels and accelerates recovery from inhibition. Chick RGS2 reduces the inhibition mediated by both the pertussis toxin (PTX)-sensitive (Gi/o-coupled) and the PTX-insensitive (presumably Gq/11-coupled) pathways. However, we demonstrate for the first time in a living cell that the extent of coupling to each pathway varies with RGS2L concentration. A low concentration of recombinant chick RGS2L (10 nM) preferentially reduces the inhibition mediated by the PTX-insensitive pathway, whereas a 100-fold higher concentration attenuates both PTX-sensitive- and PTX-insensitive-mediated components equally. Our data suggest that factors promoting RGS2L gene induction may regulate Ca2+ influx through L channels by recruiting low-affinity interactions with Gi/o that are absent at basal RGS2L levels.
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tosetti
authors.forename: Valeria
authors.initials: V
authors.lastname: Parente
authors.forename: Vanni
authors.initials: V
authors.lastname: Taglietti
authors.forename: Kathleen
authors.initials: K
authors.lastname: Dunlap
authors.forename: Mauro
authors.initials: M
authors.lastname: Toselli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002642:Chick Embryo; D003001:Cloning, Molecular; D016384:Consensus Sequence; D018076:DNA, Complementary; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D005727:Ganglia, Spinal / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009433:Neural Inhibition / Q000502:physiology; D037342:Pertussis Toxin / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation
chemical_list: D020746:Calcium Channels, L-Type; D018076:DNA, Complementary; D011506:Proteins; D020710:RGS Proteins; C476052:RGSL1 protein, human; D012333:RNA, Messenger; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D001920:Bradykinin