- Email: [email protected]
Estrogen controls energy homeostasis via a G protein-coupled signaling pathway in hypothalamic neurons
150
Abstracts / Frontiers in Neuroendocrinology 27 (2006) 148–152
ride, an ABC1 and KATP channel blocker, caused a 3-fold increase in VEGF secretion when applied alone, and greatly amplified (3-fold) the response to PACAP. Other ABC blockers did not affect VEGF secretion. Exposure of TtT/GF cells to cycloheximide prior to PACAP or glyburide abolished the increased secretion of VEGF, consistent with control of secretion via transcription. RT-PCR demonstrated that TtT/GF cells express both SUR2B and the Kir6.1 form of KATP channels. Diazoxide, a KATP activator, inhibited PACAP-stimulated VEGF secretion. These data suggest that KATP channels play a substantial role in the control of VEGF secretion and that activation of KATP channels, via cell depolarisation and calcium influx, inhibits the secretion of VEGF at the level of transcription. doi:10.1016/j.yfrne.2006.03.231
Estrogen controls energy homeostasis via a G protein-coupled signaling pathway in hypothalamic neurons Jian Qiu a, Martha A. Bosch a, Sandra C. Tobias b, Andree Krust c, Pierre Chambon c, Thomas S. Scanlan b, Oline K. Rønnekleiv a, Martin J. Kelly a a Department of Physiology and Pharmacology, Portland, OR, USA b Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, UCSF, San Francisco, CA, USA c Institute de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM, Universite Louis Pasteur, College de France, Illkirch-Cedex, France Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation, and motivated behaviors. The critical role of 17b-estradiol (E2) is evident in hypo-estrogenic states (e.g., postmenopause) where many of these functions go awry. Classically, the actions of E2 in the brain have been attributed to the activation of the intracellular estrogen receptors. However, we have identified a putative membrane-associated estrogen receptor that is Gaq-coupled to activation of a phospholipase C-protein kinase A pathway. Activation of this pathway leads to desensitization of GABAB and l-opioid receptors in hypothalamic proopiomelanocortin (POMC) neurons. Presently, we have synthesized a new non-steroidal compound, STX, that selectively targets the membrane signaling pathway and found that it is more potent than E2 in mediating this desensitization in an ICI 182, 780 sensitive manner. Both E2 and STX were fully efficacious in estrogen receptor a,b knockout mice. Moreover, in vivo treatment with STX, similar to E2, attenuated the weight gain in hypo-estrogenic female guinea pigs. Therefore, this membrane-delimited signaling pathway plays a critical role in the control
of energy homeostasis and may provide a novel therapeutic target for treatment of postmenopausal symptoms and eating disorders in females. (Supported by US Public Health Service Grants: NS43330, NS38809, DK68098, and DK57574.) doi:10.1016/j.yfrne.2006.03.232
Molecular mechanisms of relaxin action on adenylyl cyclase signaling systems using synthetic peptides, derived from relaxin receptor LGR7 Alexander Shpakov a, Ludmila Kuznetsova a, Svetlana Plesneva a, Ivan Guryanov b, Elena Shpakova a, Gennady Vlasov b, Marianna Pertseva a a I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Acad. Sci., 194223, St. Petersburg, Thorez av., 44, Russia b Institute of Macromolecular Compounds of Russian Acad. Sci., 199004, St. Petersburg, Bolshoi av., 31, Russia Relaxin stimulates adenylyl cyclase activity in a dosedependent manner in rat tissues (brain, heart, and skeletal muscles) and muscles of invertebrates—bivalve mollusk Anodonta cygnea and earthworm Lumbricus terrestris. Adenylyl cyclase stimulating effect of hormone is higher in rat brain and heart. For identification of the type of relaxin receptors participating in the realization of hormone effect, the synthetic peptides 619–629, 619–629Lys(Palm), and 615–629, derived from the primary structure of C-terminal region of the third intracellular loop of the relaxin receptor of type 1 (LGR7), were synthesized by us for the first time. It is shown that peptides 619–629-Lys(Palm) and 615–629 inhibit the stimulation of adenylyl cyclase by relaxin in rat brain and heart. However, it was found that adenylyl cyclase stimulating effects of relaxin in brain and heart was decreased in the presence of C-terminal synthetic peptides 385–394 of assubunit of mammalian G protein and was blocked by treatment of the membranes with cholera toxin. These data demonstrate the participation of receptor LGR7 in realization of adenylyl cyclase stimulating effect of relaxin in rat brain and heart. At the same time, the stimulating effect of the hormone in rat skeletal muscles and in the muscles of invertebrates was unchanged. The data give evidence for the existence of another adenylyl cyclase signaling mechanism of relaxin action in rat skeletal muscles and the muscle of invertebrates, which do not involve LGR7 receptor. Thus, the peptide action on adenylyl cyclase effects induced by relaxin is tissue and species specific. On the basis of data obtained the following conclusions were made: (i) in brain and heart, relaxin stimulates adenylyl cyclase through LGR7 receptor functionally coupled with Gs protein, and (ii) the coupling between hormone-activated relaxin receptor LGR7 and Gs protein is realized via the interaction of C-terminal part of receptor
Abstracts / Frontiers in Neuroendocrinology 27 (2006) 148–152
ride, an ABC1 and KATP channel blocker, caused a 3-fold increase in VEGF secretion when applied alone, and greatly amplified (3-fold) the response to PACAP. Other ABC blockers did not affect VEGF secretion. Exposure of TtT/GF cells to cycloheximide prior to PACAP or glyburide abolished the increased secretion of VEGF, consistent with control of secretion via transcription. RT-PCR demonstrated that TtT/GF cells express both SUR2B and the Kir6.1 form of KATP channels. Diazoxide, a KATP activator, inhibited PACAP-stimulated VEGF secretion. These data suggest that KATP channels play a substantial role in the control of VEGF secretion and that activation of KATP channels, via cell depolarisation and calcium influx, inhibits the secretion of VEGF at the level of transcription. doi:10.1016/j.yfrne.2006.03.231
Estrogen controls energy homeostasis via a G protein-coupled signaling pathway in hypothalamic neurons Jian Qiu a, Martha A. Bosch a, Sandra C. Tobias b, Andree Krust c, Pierre Chambon c, Thomas S. Scanlan b, Oline K. Rønnekleiv a, Martin J. Kelly a a Department of Physiology and Pharmacology, Portland, OR, USA b Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, UCSF, San Francisco, CA, USA c Institute de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM, Universite Louis Pasteur, College de France, Illkirch-Cedex, France Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation, and motivated behaviors. The critical role of 17b-estradiol (E2) is evident in hypo-estrogenic states (e.g., postmenopause) where many of these functions go awry. Classically, the actions of E2 in the brain have been attributed to the activation of the intracellular estrogen receptors. However, we have identified a putative membrane-associated estrogen receptor that is Gaq-coupled to activation of a phospholipase C-protein kinase A pathway. Activation of this pathway leads to desensitization of GABAB and l-opioid receptors in hypothalamic proopiomelanocortin (POMC) neurons. Presently, we have synthesized a new non-steroidal compound, STX, that selectively targets the membrane signaling pathway and found that it is more potent than E2 in mediating this desensitization in an ICI 182, 780 sensitive manner. Both E2 and STX were fully efficacious in estrogen receptor a,b knockout mice. Moreover, in vivo treatment with STX, similar to E2, attenuated the weight gain in hypo-estrogenic female guinea pigs. Therefore, this membrane-delimited signaling pathway plays a critical role in the control
of energy homeostasis and may provide a novel therapeutic target for treatment of postmenopausal symptoms and eating disorders in females. (Supported by US Public Health Service Grants: NS43330, NS38809, DK68098, and DK57574.) doi:10.1016/j.yfrne.2006.03.232
Molecular mechanisms of relaxin action on adenylyl cyclase signaling systems using synthetic peptides, derived from relaxin receptor LGR7 Alexander Shpakov a, Ludmila Kuznetsova a, Svetlana Plesneva a, Ivan Guryanov b, Elena Shpakova a, Gennady Vlasov b, Marianna Pertseva a a I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Acad. Sci., 194223, St. Petersburg, Thorez av., 44, Russia b Institute of Macromolecular Compounds of Russian Acad. Sci., 199004, St. Petersburg, Bolshoi av., 31, Russia Relaxin stimulates adenylyl cyclase activity in a dosedependent manner in rat tissues (brain, heart, and skeletal muscles) and muscles of invertebrates—bivalve mollusk Anodonta cygnea and earthworm Lumbricus terrestris. Adenylyl cyclase stimulating effect of hormone is higher in rat brain and heart. For identification of the type of relaxin receptors participating in the realization of hormone effect, the synthetic peptides 619–629, 619–629Lys(Palm), and 615–629, derived from the primary structure of C-terminal region of the third intracellular loop of the relaxin receptor of type 1 (LGR7), were synthesized by us for the first time. It is shown that peptides 619–629-Lys(Palm) and 615–629 inhibit the stimulation of adenylyl cyclase by relaxin in rat brain and heart. However, it was found that adenylyl cyclase stimulating effects of relaxin in brain and heart was decreased in the presence of C-terminal synthetic peptides 385–394 of assubunit of mammalian G protein and was blocked by treatment of the membranes with cholera toxin. These data demonstrate the participation of receptor LGR7 in realization of adenylyl cyclase stimulating effect of relaxin in rat brain and heart. At the same time, the stimulating effect of the hormone in rat skeletal muscles and in the muscles of invertebrates was unchanged. The data give evidence for the existence of another adenylyl cyclase signaling mechanism of relaxin action in rat skeletal muscles and the muscle of invertebrates, which do not involve LGR7 receptor. Thus, the peptide action on adenylyl cyclase effects induced by relaxin is tissue and species specific. On the basis of data obtained the following conclusions were made: (i) in brain and heart, relaxin stimulates adenylyl cyclase through LGR7 receptor functionally coupled with Gs protein, and (ii) the coupling between hormone-activated relaxin receptor LGR7 and Gs protein is realized via the interaction of C-terminal part of receptor