Publikationsserver der Universitätsbibliothek Marburg
Titel:Pertussistoxin-sensitive Signalwege von alpha-MSH und AgRP an Melanocortin-4-Rezeptoren
Autor:Heling, Dominik Johannes
Weitere Beteiligte: Gudermann, Thomas (Prof. Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/0970
URN: urn:nbn:de:hebis:04-z2012-09701
DOI: https://doi.org/10.17192/z2012.0970
DDC:610 Medizin
Titel (trans.):Pertussistoxin-sensitive signalling of alpha-MSH and AgRP at the Melanocortin-4-Receptor
Publikationsdatum:2012-11-05
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Melanocortin-4-Rezeptor, Melanocortin-4 receptor

Zusammenfassung:
Der Melanocortin-4-Rezeptor (MC4R) ist ein G-Protein-gekoppelter Rezeptor (GP- CR), dessen Signaltransduktion von zentraler Bedeutung für die Regulation der Körpergewichtshomöostase im Hypothalamus ist. Mutationen im MC4R sind die häufigste monogenetische Ursache für Adipositas. Bislang wurde die Signal- wirkung des MC4R ausschließlich seiner Gs-Kopplung und dadurch bedingten cAMP-Akkumulation zugeschrieben. Der endogene MC4R-Agonist „Ð-Melanozyten- stimulierendes Hormon“ (Ð-MSH) wirkt anorexigen über eine Gs-Protein-bedingte Steigerung der cAMP-Produktion. In Übereinstimmung hiermit ist die Mutation D90N des MC4R, welche keine Gs-Proteine aktiviert, assoziiert mit einer ausgepräg- ten Adipositas. Eine Besonderheit des MC4R ist das Vorkommen von endogenen Antagonisten: „Agouti-related Protein“ (AgRP) wirkt zum einen durch die Blockade der Ð-MSH-Wirkung indirekt orexigen, kann aber auch in Abwesenheit von Ð-MSH basale cAMP-Spiegel erniedrigen. Daher wird AgRP auch eine inverse agonistische Wirkung zugesprochen. Interessanterweise ist weder die physiologische Bedeutung dieser Wirkung bekannt, noch sind die dazu führenden Mechanismen verstanden. Zur Untersuchung der detaillierten molekularen Wirkung von Ð-MSH und AgRP auf den MC4R wurde die G-Protein-Aktivierung mittels GTPÒ35S-Assay, sowie die cAMP-Akkumulation mittels cAMP-Assay in HEK293-Zellen und GT1-7-Zellen un- tersucht. Überraschenderweise konnte in dieser Arbeit gezeigt werden, dass neben Ð- 110 5. Zusammenfassung MSH auch AgRP G-Proteine aktiviert und somit agonistisch am MC4R wirkt. Diese AgRP-bedingte G-Protein-Aktivierung war PTX-sensitiv, welches die aktivierten G- Proteine als Gi/o-Proteine kennzeichnet. Auch die Aktivierung von PTX-sensitiven G-Proteinen an der Gs-defizienten D90N-Mutation belegt die Involvierung von Gi/o- Proteinen bei der Signaltransduktion des MC4R im Allgemeinen. Somit konnte in dieser Arbeit eine duale Kopplung des MC4Rs an Gi/o- und Gs-Proteine in einem endogenen Zellsystem etabliert werden. AgRP ist in der Lage selektiv Gi/o-Proteine zu aktivieren und damit aktiv, Ð-MSH-unabhängig die Körpergewichtshomöostase zu regulieren. Neben diesem wichtigen Befund für das Melanocortinsystem, besitzt die Definition der AgRP-Wirkung, als endogen vorkommender funktional selektiver Agonist an einem etablierten GPCR, große Bedeutung für das Verständnis dieser Rezeptorfamilie im Allgemeinen.

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