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Regulation Von TRPM3 Durch Α2-Adrenorezeptoren in Pankreatischen Β-Zellen

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Regulation Von TRPM3 Durch Α2-Adrenorezeptoren in Pankreatischen Β-Zellen Aus dem Institut für Physiologie und Pathophysiologie Geschäftsführender Direktor: Prof. Dr. Dr. Daut AG Molekulare Physiologie des Fachbereiches Medizin der Philipps-Universität Marburg Regulation von TRPM3 durch α2-Adrenorezeptoren in pankreatischen β-Zellen Inaugural-Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften dem Fachbereich Medizin der Philipps-Universität Marburg vorgelegt von Florian Mohr (geb. in Saarbrücken) Marburg, 2014 Angenommen vom Fachbereich Medizin der Philipps-Universität Marburg am: 07.03.2014 Gedruckt mit Genehmigung des Fachbereichs. Dekan: Prof. Dr. Helmut Schäfer Referent: Prof. Dr. Johannes Oberwinkler 1. Korreferent: Prof. Dr. Patrick Michl 2 Zusammenfassung Zusammenfassung TRPM3 ist ein Ca2+-permeabler, nichtselektiver Kationenkanal der TRP-Familie, der durch das endogene Neurosteroid Pregnenolonsulfat aktiviert werden kann. Eine funktionelle Expression des Kanals konnte unter anderem in pankreatischen β-Zellen nachgewiesen werden. Eine Aktivierung von TRPM3 in β-Zellen führt zu einem Einstrom von Ca2+ und zu einer Verstärkung der Glucose-induzierten Insulinfreisetzung. Die genaue Funktion des Kanals im Kontext der β-Zellen ist jedoch noch nicht vollständig verstanden. Die Insulinfreisetzung in β-Zellen unterliegt einer äußerst strikten und vielseitigen Regulation und wird präzise den physiologischen Begebenheiten angepasst. Viele dieser Modulationen werden hierbei über G-Protein gekoppelte Rezeptoren (GPCR) vermittelt. Da für viele TRP-Kanäle bekannt ist, dass sie durch GPCR moduliert werden und die überwiegende Mehrheit der an der Insulinfreisetzung beteiligten Ionenkanäle durch GPCR auf die eine oder andere Art moduliert werden, stellte sich die Frage, ob auch TRPM3 in β-Zellen einer solchen Regulation unterliegt. Es zeigte sich, dass die Aktivität von TRPM3 in β-Zellen und Ins1 Zellen (Insulinoma Zelllinie der Ratte) durch Noradrenalin stark und reversibel inhibiert wird. Durch pharmakologische Experimente konnte nachgewiesen werden, dass die Hemmung dabei über α2-Adrenorezeptoren vermittelt wird. Eine genauere Betrachtung des zugrundeliegenden Signalwegs offenbarte, dass die TRPM3-Hemmung durch einen Gαi/o-gekoppelten Mechanismus induziert wird. Eine Beteiligung des „klassischen“, cAMP-abhängigen Signalwegs konnte ausgeschlossen werden. In Überexpressions- experimenten zeigte sich weiterhin, dass aktivierte Gαi/o-Untereinheiten nicht an der direkten Vermittlung der Inhibition beteiligt sind. Eine Überexpression von βγ- Untereinheiten hingegen führte zu einer drastischen Verminderung der TRPM3- Aktivität. Jedoch konnten nicht alle βγ-Kombinationen die TRPM3-Hemmung induzieren. Lediglich β1 und β2, in Kombination mit einer γ-Untereinheit, waren in der Lage, die TRPM3-Aktivität zu inhibieren. Ebenso konnte in Ins1 Zellen, die mit mSIRK (einem membrangängigen Peptid, das eine Freisetzung von βγ-Untereinheiten induziert) behandelt wurden, eine Reduktion der TRPM3-Aktivität beobachtet werden. 3 Zusammenfassung Weiterhin konnte durch Abfangen von βγ-Untereinheiten (mittels myr-Phosducin oder myr-βARKct (Polypeptide, die βγ-Untereinheiten direkt binden)) die Noradrenalin vermittelte TRPM3-Hemmung deutlich abgeschwächt werden. Eine Beteiligung der PLC, der PKC, der PLA2 und löslichen, cytosolischen Faktoren am Signalweg, der zur TRPM3-Hemmung führt, konnte hingegen weitgehend ausgeschlossen werden. Somit besteht die Möglichkeit, dass die Noradrenalin-induzierte Hemmung der TRPM3- Kanäle auf eine direkte Interaktion der βγ-Untereinheiten mit TRPM3 zurückzuführen ist. Es zeigte sich, dass nicht alle TRPM3-Spleißvarianten sensitiv für die durch α2- Adrenorezeptor vermittelte Inhibition sind bzw. nicht alle eine verminderte Aktivität nach Überexpression von βγ-Untereinheiten aufweisen. Dafür verantwortlich scheint eine 10 Aminosäure lange Sequenz zu sein, die durch Exon 17 kodiert wird und in den insensitiven Spleißvarianten (TRPM3α4 und TRPM3α5) nicht vorhanden ist. Die vorliegende Arbeit zeigt deutlich, dass TRPM3 in β-Zellen einer starken Regulierung durch α2-Adrenorezeptoren unterliegt. Dies deutet darauf hin, dass TRPM3 möglicherweise eine essentielle Funktion in β-Zellen besitzt, die einer ausgeprägten sympathischen Regulation bedarf. Die gewonnenen Erkenntnisse tragen somit zu einem besseren Verständnis der TRPM3-Kanäle im Kontext der β-Zellen bei. Die Entdeckung, dass TRPM3 durch Gαi/o-gekoppelte GPCR moduliert werden kann, stellt ebenso eine wichtige Grundlage für nachfolgende Untersuchungen bezüglich der Rolle, Funktion und Regulation von TRPM3 in anderen Geweben dar. 4 Summary Summary TRPM3 is a Ca2+ permeable nonselective cation channel of the transient receptor potential melastatin channel family. The channel is expressed in pancreatic β cells and can be activated by the endogenous neurosteroid pregnenolone sulphate. The activation of TRPM3 in pancreatic β cells leads to calcium influx followed by an enhanced glucose-stimulated insulin release. However, the physiological functions of TRPM3 in pancreatic β cells are not well understood so far. Insulin release in β cells is subject to strong and diverse regulation and can be adapted to different physiological conditions. Many of these regulations are mediated by G-protein coupled receptors (GPCR). It is well known that various TRP channels and most of the ion channels in β cells are regulated by GPCR. The question arose whether TRPM3 activity in β cells is also subject to such a regulation or modulation. Indeed, in primary pancreatic β cells and rat insulinoma cells (Ins1) noradrenaline strongly and reversibly inhibits the TRPM3 activity and pharmacological experiments revealed that the inhibition is mediated via α2-adrenoreceptors. Intrigued by this effect we decided to take a closer look at the intracellular signaling cascades that mediates the TRPM3 inhibition in pancreatic β cells. Experiments with pertussis toxin (PTX), an inhibitor of Gi/o-proteins, revealed that the mechanism is Gi/o-protein coupled. However, we could rule out a classical regulation by alteration of intracellular cAMP levels. Also a direct interaction of Gαi/o subunits with the channel could be excluded through overexpression experiments. By contrast, overexpression of βγ-subunits leads to a strong inhibition of the TRPM3 activity. But only β1 or β2 co-expressed with a γ- subunit were able to strongly inhibit the channel. Furthermore Ins1 cells treated with mSIRK (a membrane permeable peptide that induces a release of βγ-subunits) showed a strong reduction of the TRPM3 activity. Additional experiments with βγ-scavenging peptides (myr-phosducin or myr-βARKct) also led to a reduction of the inhibitory noradrenaline effect. A participation of PLC, PKC, PLA2 and soluble cytosolic factors in the signaling pathway that induces the inhibition of TRPM3 could be largely excluded in further experiments, indicating that βγ-subunits could perhaps directly induce the inhibition of the channel. 5 Summary It turned out that not all TRPM3 splice variants show a α2-adrenoreceptor mediated inhibition or decrease of activity after overexpression of βγ-subunits. It seems that a sequence of 10 amino acids (coded by exon 17) is required for the channel inhibition, since splice variants without this sequence (TRPM3α4 and TRPM3α5) were insensitive to α2-adrenoreceptor mediated inhibition and overexpression of βγ-subunits and showed no reduction of the channel activity. This study clearly shows that TRPM3 is strongly regulated by α2-adrenoreceptors in β cells. Indicating that TRPM3 may play an important part in pancreatic β cells which necessitates strict sympathetic regulation. The results obtained in this study contribute to a better understanding of the function of TRPM3 in β cells. Furthermore, the discovery that TRPM3 can be modulated via Gαi/o-coupled GPCR provides a basis for further investigation of the role, function and regulation of TRPM3 in other tissues. 6 Inhaltsverzeichnis Inhaltsverzeichnis Zusammenfassung .......................................................................................................................3 Summary ......................................................................................................................................5 Inhaltsverzeichnis .........................................................................................................................7 1. Einleitung ...............................................................................................................................10 1.1 TRP-Kanäle .......................................................................................................................10 1.2 TRPM-Unterfamilie ...........................................................................................................13 1.3 TRPM3 ..............................................................................................................................14 1.4 Pankreas und Langerhans-Inseln ......................................................................................17 1.5 β-Zellen und Insulinfreisetzung ........................................................................................19 1.6 GPCR .................................................................................................................................21 1.7 G-Proteine ........................................................................................................................22 1.8 Gα-Untereinheiten ...........................................................................................................23
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