In the conventional model of α-MSH/AgRP signaling at PVN MC4R neurons, AgRP acts as a competitive inhibitor to block α-MSH stimulation of Gαs and as an inverse agonist to block constitutive signaling through this pathway (central orange box). Ghamari-Langroudi et al. (2015) propose that AgRP also acts as an agonist at MC4R to activate Kir7.1, and thereby hyperpolarize the cell independently of α-MSH and the Gαs pathway (left circle). At some sites, α-MSH may act independently of AgRP to stimulate Gαs signaling and also to close Kir7.1 (right circle). In the dorsal motor nucleus of the vagus (DMV), α-MSH activates KATP channels through a Gαs pathway (lower right). (Reprinted by permission from Macmillan Publishers, Ltd. M. Ghamari-Langroudi et al. Nature. http://dx.doi.org/10.1038/nature14051, copyright 2015.)

In the conventional model of α-MSH/AgRP signaling at PVN MC4R neurons, AgRP acts as a competitive inhibitor to block α-MSH stimulation of Gαs and as an inverse agonist to block constitutive signaling through this pathway (central orange box). Ghamari-Langroudi et al. (2015) propose that AgRP also acts as an agonist at MC4R to activate Kir7.1, and thereby hyperpolarize the cell independently of α-MSH and the Gαs pathway (left circle). At some sites, α-MSH may act independently of AgRP to stimulate Gαs signaling and also to close Kir7.1 (right circle). In the dorsal motor nucleus of the vagus (DMV), α-MSH activates KATP channels through a Gαs pathway (lower right). (Reprinted by permission from Macmillan Publishers, Ltd. M. Ghamari-Langroudi et al. Nature. http://dx.doi.org/10.1038/nature14051, copyright 2015.)

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