title: Melanocortin 4 receptor constitutive activity inhibits L-type voltage-gated calcium channels in neurons.
abstract: The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain nuclei playing a crucial role in the regulation of energy balance controlling the homeostasis of the organism. It displays both agonist-evoked and constitutive activity, and moreover, it can couple to different G proteins. Most of the research on MC4R has been focused on agonist-induced activity, while the molecular and cellular basis of MC4R constitutive activity remains scarcely studied. We have previously shown that neuronal N-type voltage-gated calcium channels (CaV2.2) are inhibited by MC4R agonist-dependent activation, while the CaVsubtypes that carry L- and P/Q-type current are not. Here, we tested the hypothesis that MC4R constitutive activity can affect CaV, with focus on the channel subtypes that can control transcriptional activity coupled to depolarization (L-type, CaV1.2/1.3) and neurotransmitter release (N- and P/Q-type, CaV2.2 and CaV2.1). We found that MC4R constitutive activity inhibits specifically CaV1.2/1.3 and CaV2.1 subtypes of CaV. We also explored the signaling pathways mediating this inhibition, and thus propose that agonist-dependent and basal MC4R activation modes signal differentially through Gsand Gi/opathways to impact on different CaVsubtypes. In addition, we found that chronic incubation with MC4R endogenous inverse agonist, agouti and agouti-related peptide (AgRP), occludes CaVinhibition in a cell line and in amygdaloid complex cultured neurons as well. Thus, we define new mechanisms of control of the main mediators of depolarization-induced calcium entry into neurons by a GPCR that displays constitutive activity.
authors.affiliation: Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology (IMBICE) Universidad de La Plata-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comision de Investigaciones de la Provincia de buenos Aires (CIC), La Plata, Buenos Aires, Argentina.
authors.forename: F
authors.initials: F
authors.lastname: Agosti
authors.affiliation: Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology (IMBICE) Universidad de La Plata-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comision de Investigaciones de la Provincia de buenos Aires (CIC), La Plata, Buenos Aires, Argentina.
authors.forename: S
authors.initials: S
authors.lastname: Cordisco Gonzalez
authors.affiliation: Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology (IMBICE) Universidad de La Plata-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comision de Investigaciones de la Provincia de buenos Aires (CIC), La Plata, Buenos Aires, Argentina.
authors.forename: V
authors.initials: V
authors.lastname: Martinez Damonte
authors.affiliation: Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology (IMBICE) Universidad de La Plata-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comision de Investigaciones de la Provincia de buenos Aires (CIC), La Plata, Buenos Aires, Argentina.
authors.forename: M J
authors.initials: MJ
authors.lastname: Tolosa
authors.affiliation: Instituto de Investigaciones Farmacológicas, ININFA, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, Buenos Aires, Argentina.
authors.forename: N
authors.initials: N
authors.lastname: Di Siervi
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.
authors.forename: H B
authors.initials: HB
authors.lastname: Schioth
authors.affiliation: Instituto de Investigaciones Farmacológicas, ININFA, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, Buenos Aires, Argentina.
authors.forename: C
authors.initials: C
authors.lastname: Davio
authors.affiliation: Neurophysiology Laboratory, Multidisciplinary Institute of Cell Biology (IMBICE) Universidad de La Plata-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comision de Investigaciones de la Provincia de buenos Aires (CIC), La Plata, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Perello
authors.affiliation: Electrophysiology Laboratory, Multidisciplinary Institute of Cell Biology (IMBICE) Universidad de La Plata-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, and Comision de Investigaciones de la Provincia de buenos Aires (CIC), La Plata, Buenos Aires, Argentina.
authors.forename: J
authors.initials: J
authors.lastname: Raingo
mesh_terms: D054369:Agouti-Related Protein / Q000008:administration & dosage; D000679:Amygdala / Q000378:metabolism / Q000502:physiology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C515198:AGRP protein, human; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D020746:Calcium Channels, L-Type; C470072:MC4R protein, human; C574273:MC4R protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D044105:Receptor, Melanocortin, Type 4; D019204:GTP-Binding Proteins
keywords: G protein; amygdala; calcium channels; electrophysiology; melanocortin receptor