Modulation of the beta-adrenergic-response in cultured rat heart cells. II. Mammary-derived growth inhibitor (MDGI) blocks induction of beta-adrenergic supersensitivity. Dissociation from lipid-binding activity of MDGI.
'Mammary-derived growth inhibitor (MDGI)' is a 14.5 kDa polypeptide with growth-inhibitory activity for various mammary epithelial cells in vitro which is highly homologous to cardiac fatty acid-binding protein (H-FABP). Here we describe a new biological activity of MDGI: Inhibition of L(+)-lactate-, arachidonic acid- and 15-S-hydroxyeicosatetraenoic acid-induced supersensitivity of neonatal rat heart cells for beta-adrenergic stimulation, concerning particularly a small population of beta 2-receptors. Synthetic peptides corresponding to the MDGI-sequence, residue 121-131 mimic the effect of MDGI. Measurements of lipid-binding to MDGI and synthetic peptides excluded the binding of arachidonic acid, 15-S-hydroxyeicosatetraenoic acid or beta-adrenergic agonists to MDGI or the peptides as the mechanism for this effect. Also, no direct interference of MDGI and the synthetic peptides with the binding of the beta-adrenergic agent CGP 12177 to its receptor on A431 cells could be detected. We suggest that MDGI and the peptides act by interference with the function of the beta 2-adrenergic receptor and that this mechanism might also be relevant for the growth-inhibitory activity of MDGI. Furthermore, the data point to a possible function of H-FABP for the modulation of beta-adrenergic sensitivity of cardiac myocytes.
Wallukat
G
G
Central Institute for Cardiovascular Research, Academy of Sciences, Berlin-Buch, Germany.
Boehmer
F D
FD
Engstroem
U
U
Langen
P
P
Hollenberg
M
M
Behlke
J
J
Kuehn
H
H
Grosse
R
R
D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000074026:Fatty Acid Binding Protein 3; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D006131:Growth Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007545:Isoproterenol / Q000037:antagonists & inhibitors*; D007773:Lactates / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology; D011457:Prostaglandins D / Q000037:antagonists & inhibitors; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D001095:Arachidonic Acids; D002352:Carrier Proteins; C509948:FABP3 protein, rat; C493409:Fabp3 protein, mouse; C490174:Fabp7 protein, rat; D000074026:Fatty Acid Binding Protein 3; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D006131:Growth Inhibitors; D007773:Lactates; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D011412:Propanolamines; D011457:Prostaglandins D; D011943:Receptors, Adrenergic, beta; D016718:Arachidonic Acid; D007545:Isoproterenol; C033394:CGP 12177