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PROTEIN CHEMISTRY AND STRUCTUREAntagonists of the Receptor-G Protein Interface Block Gi-coupled Signal Transduction*Under a Creative Commons license Open access The carboxyl terminus of heterotrimeric G protein α subunits plays an important role in receptor interaction. We demonstrate that peptides corresponding to the last 11 residues of Gαi1/2 or Gαo1 impair agonist binding to A1 adenosine receptors, whereas Gαs or Gαt peptides have no effect. Previously, by using a combinatorial library we identified a series of Gαtpeptide analogs that bind rhodopsin with high affinity (Martin, E. L., Rens-Domiano, S., Schatz, P. J., and Hamm, H. E. (1996)J. Biol. Chem. 271, 361–366). Native Gαi1/2 peptide as well as several analogs were tested for their ability to modulate agonist binding or antagonist-agonist competition using cells overexpressing human A1 adenosine receptors. Three peptide analogs decreased the K i, suggesting that they disrupt the high affinity receptor-G protein interaction and stabilize an intermediate affinity state. To study the ability of the peptides to compete with endogenous Gαiproteins and block signal transduction in a native setting, we measured activation of G protein-coupled K+ channels through A1 adenosine or γ-aminobutyric acid, type B, receptors in hippocampal CA1 pyramidal neurons. Native Gαi1/2, peptide, and certain analog peptides inhibited receptor-mediated K+ channel gating, dependent on which receptor was activated. This differential perturbation of receptor-G protein interaction suggests that receptors that act on the same G protein can be selectively disrupted. Cited by (0)© 1998 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. Afghanistan, Albania, Algeria, Andorra, Angola, Anguilla, Argentina, Armenia, Azerbaijan Republic, Belarus, Benin, Bhutan, Bosnia and Herzegovina, Botswana, Brazil, British Virgin Islands, Burkina Faso, Burundi, Cameroon, Cape Verde Islands, Central African Republic, Chad, Comoros, Congo, Democratic Republic of the, Congo, Republic of the, Cook Islands, Côte d'Ivoire (Ivory Coast), Djibouti, Ecuador, Equatorial Guinea, Eritrea, Ethiopia, Falkland Islands (Islas Malvinas), Fiji, French Polynesia, Gabon Republic, Gambia, Georgia, Ghana, Greenland, Guinea, Guinea-Bissau, Guyana, Haiti, India, Iraq, Kazakhstan, Kenya, Kiribati, Kyrgyzstan, Laos, Lebanon, Lesotho, Liberia, Libya, Macedonia, Madagascar, Malawi, Malaysia, Mali, Marshall Islands, Mauritania, Mauritius, Mayotte, Micronesia, Moldova, Mongolia, Montenegro, Morocco, Mozambique, Namibia, Nauru, Nepal, Netherlands Antilles, New Caledonia, Niger, Nigeria, Niue, Palau, Papua New Guinea, Peru, Russian Federation, Rwanda, Saint Helena, Saint Pierre and Miquelon, Saint Vincent and the Grenadines, San Marino, Senegal, Serbia, Seychelles, Sierra Leone, Solomon Islands, Somalia, Suriname, Svalbard and Jan Mayen, Swaziland, Tajikistan, Tanzania, Thailand, Togo, Tonga, Tunisia, Turkey, Turkmenistan, Tuvalu, Uganda, Ukraine, Uzbekistan, Vanuatu, Vatican City State, Venezuela, Vietnam, Virgin Islands (U.S.), Wallis and Futuna, Western Sahara, Western Samoa, Yemen, Zambia, Zimbabwe
Pharmacological Activation Gi/o Protein Increases Glial Cell Line-Derived Neurotrophic Factor Production through Fibroblast Growth Factor Receptor and Extracellular Signal-Regulated Kinase Pathway in Primary Cultured Rat Cortical AstrocytesKazue Hisaoka-Nakashima et al. Biol Pharm Bull. 2017. Free article AbstractA significant reduction of glial cell line-derived neurotrophic factor (GDNF) has been identified in the pathophysiology of neurodegenerative and neuropsychiatric disorders. Thus, clarification of the mechanism of GDNF production, and modulating brain GDNF levels could be a novel therapeutic approach. A previous study demonstrated that antidepressant amitriptyline-induced GDNF production was significantly inhibited by pertussis toxin (PTX), a Gi/o protein inhibitor in astrocytes, the main source of GDNF in the brain. However, it is not known whether direct activation of Gi/o protein might induce GDNF expression, and what mechanisms might be involved after Gi/o protein activation. The current study investigated Gi/o protein-initiated GDNF production in rat cortical astrocytes using activators that directly activate Gi/o protein, mastoparan and compound48/80. Treatment of astrocytes with either mastoparan or compound48/80 increased GDNF mRNA expression at 3 and 6 h, and GDNF protein release at 24 h. Treatment of astrocyte with either mastoparan or compound48/80 increased brain-derived neurotrophic factor (BDNF) mRNA expression as well as GDNF. Mastoparan and compound48/80-induced GDNF mRNA expression were significantly inhibited by not only PTX, but also fibroblast growth factor receptor (FGFR) inhibitors, and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor. In fact, both FGFR substrate2α (FRS2α) and ERK phosphorylation were increased by treatment with either mastoparan or compound48/80, and these were significantly blocked by PTX. Thus, direct, receptor-independent Gi/o protein activation increases GDNF production through FGFR/ERK signaling pathway. The current results indicate a critical role of Gi/o signaling in the regulation of GDNF expression in astrocytes. Keywords: Gi/o protein; astrocyte; brain-derived neurotrophic factor; glial cell line-derived neurotrophic factor; neurodegenerative disorder; neuropsychiatric disorder. Similar articles
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