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jgp Home » 2015 Archive » 1 September » 146 (3): 201
Commentary

All roads lead to presynaptic calcium channel inhibition by the ghrelin receptor: Separate agonist-dependent and -independent signaling pathways

Norbert Weiss, Gerald W. Zamponi
Norbert Weiss
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 199 00 Prague 9, Czech Republic
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Gerald W. Zamponi
Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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DOI: 10.1085/jgp.201511462 | Published August 17, 2015
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    Figure 1.

    Ghrelin receptor signaling in the hypothalamus. (A) Hypothalamic circuits involved in ghrelin-mediated feeding behavior. Two distinct neuronal populations in the ARC represented by ArGP/NPY/GABA neurons and POMC/CART neurons are considered first-order sensory neurons in the control of food intake. They project to anorexigenic neurons in the PVN and orexigenic neurons in the PFA and LHA, which in turn project to the NTS to control feeding behavior. Upon stimulation of ArGP/NPY/GABA neuron activity by ghrelin, POMC/CART neurons are inhibited through GABAergic input from activated ArGP/NPY/GABA neurons, which in turn suppress the anorexigenic tone in the PVN. This inhibition may be balanced by the inhibition of Cav2.1 and Cav2.2 channels on the ArGP/NPY/GABA neurons by presynaptic GHSR1a (dotted circle). This in turn inhibits GABA release and suppresses inhibitory GABAergic input of POMC/CART neurons. The orexigenic and anorexigenic pathways are outlined in green (plus symbols) and red (minus symbols), respectively. (B) GHSR1a-mediated inhibition of presynaptic Cav2.1 and Cav2.2 channels occurs via two distinct mechanisms: (1) an agonist-dependent inhibition that involves the activation of Gαq-coupled receptors and a direct channel inhibition by Gβγ dimer; and (2) an agonist-independent inhibition mediated by constitutive GHSR1a activity and Gαi/o signaling that not only supports Gβγ-mediated inhibition but also decreases channel density in the plasma membrane, possibly by stimulating the internalization of channel–receptor complexes or by suppressing channel trafficking to the cell surface.

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All roads lead to presynaptic calcium channel inhibition by the ghrelin receptor: Separate agonist-dependent and -independent signaling pathways
Norbert Weiss, Gerald W. Zamponi
The Journal of General Physiology Sep 2015, 146 (3) 201-204; DOI: 10.1085/jgp.201511462

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The Journal of General Physiology: 151 (2)

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February 4, 2019
Volume 151, No. 2

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