title: Enhancing and limiting endothelin-1 signaling with a cell-penetrating peptide mimicking the third intracellular loop of the ETB receptor.
abstract: TAT (a 13-mer derived from the HIV-1 Tat protein)-linked cell-permeable peptides deliver plasma membrane impermeable cargos into the cell. We investigated the effect of a TAT-linked intracellular third loop of the endothelin-1 type B receptor on endothelin-1 activation of ERK. The effect of this peptide on ERK activation was determined in ETB receptor cDNA-transfected Chinese hamster ovary cells and in ETA- and ETB-expressing human pulmonary artery smooth muscle cells obtained from a normal and a bone morphogenetic protein-2 receptor, exon 1-8 deletion subject, with pulmonary hypertension. In the Chinese hamster ovary cells the peptide, at optimum 10 μm concentration, suppressed endothelin-1 activation. In the normal human pulmonary artery smooth muscle cells, the peptide marginally enhanced endothelin-1 activation of ERK. However, it markedly enhanced the endothelin-1 activation of ERK in the bone morphogenetic protein-2 receptor human pulmonary artery smooth muscle cells. While the effective concentration for endothelin-1 activation of ERK remained unchanged in the bone morphogenetic protein-2 receptor human pulmonary artery smooth muscle cells, the number of ETB receptors declined by 2/3. These data point to the intracellular third loop peptide as having variable receptor interactive effects with both signal repressive and enhancing capabilities. Peptides that can alter endothelin-1 signal capabilities are potentially important in the study and treatment of pulmonary hypertension.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, MA 02118, USA.
authors.forename: Christine O
authors.initials: CO
authors.lastname: Sallum
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Wilson
authors.forename: Chamila
authors.initials: C
authors.lastname: Rupasinghe
authors.forename: Eric
authors.initials: E
authors.lastname: Berg
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Green
authors.forename: Linda
authors.initials: L
authors.lastname: Taylor
authors.forename: Dale
authors.initials: D
authors.lastname: Mierke
authors.forename: Peter
authors.initials: P
authors.lastname: Polgar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D016466:CHO Cells; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D006224:Cricetinae; D019332:Endothelin-1 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015696:Gene Products, tat / Q000737:chemistry; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D011651:Pulmonary Artery / Q000166:cytology; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000737:chemistry* / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; D019332:Endothelin-1; D015696:Gene Products, tat; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D048049:Extracellular Signal-Regulated MAP Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II