title: Alpha-adrenergic receptors regulate human lymphocyte amiloride-sensitive sodium channels.
abstract: Two independent signal transduction pathways regulate lymphocyte amiloride-sensitive sodium channels (ASSCs), one utilizing cAMP as a second messenger and the other utilizing a GTP-binding protein. This implies that two plasma membrane receptors play a role in the regulation of lymphocyte ASSCs. In this study, we tested the hypothesis that alpha1- and alpha2-adrenergic receptors independently regulate lymphocyte ASSCs via the two previously identified second messengers. Direct measurements indicated that norepinephrine increased lymphocyte cAMP and activated ASSCs. The alpha2-specific inhibitor, yohimbine, blocked this activation, thereby linking alpha2-adrenergic receptors to ASSC regulation via cAMP. The alpha1-specific ligand, terazosin, acted as an agonist and activated lymphocyte ASSCs but inhibited ASSC current that had been preactivated by norepinephrine or 8-(4-chlorophenylthio) (CPT)-cAMP. Terazosin had no effect on the lymphocyte whole cell ASSC currents preactivated by treatment with pertussis toxin. This finding indirectly links alpha1-adrenergic receptors to lymphocyte ASSC regulation via GTP-binding proteins. Terazosin had no direct inhibitory or stimulatory effects on alpha,beta,gamma-endothelial sodium channels reconstituted into planar lipid bilayers and expressed in Xenopus oocytes, ruling out a direct interaction between terazosin and the channels. These findings support the hypothesis that both alpha1- and alpha2-adrenergic receptors independently regulate lymphocyte ASSCs via GTP-binding proteins and cAMP, respectively.
authors.affiliation: Department of Physiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Bubien
authors.forename: T
authors.initials: T
authors.lastname: Cornwell
authors.forename: A L
authors.initials: AL
authors.lastname: Bradford
authors.forename: C M
authors.initials: CM
authors.lastname: Fuller
authors.forename: M D
authors.initials: MD
authors.lastname: DuVall
authors.forename: D J
authors.initials: DJ
authors.lastname: Benos
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000584:Amiloride / Q000494:pharmacology*; D000818:Animals; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D017292:Doxazosin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D053503:Epithelial Sodium Channels; D019204:GTP-Binding Proteins / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015222:Sodium Channels / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D053503:Epithelial Sodium Channels; D011942:Receptors, Adrenergic, alpha; D011994:Recombinant Proteins; D015222:Sodium Channels; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000584:Amiloride; C041226:Terazosin; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D007545:Isoproterenol; D017292:Doxazosin; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine; D011224:Prazosin