Influence of GPCR coexpression in neuronal cells on the convergence of signaling pathways

Ullrich, Tim

dc.contributor.advisor	Salonikidis, Petrus S. Dr.	de
dc.contributor.author	Ullrich, Tim	de
dc.date.accessioned	2013-07-18T09:45:06Z	de
dc.date.available	2013-08-05T22:50:04Z	de
dc.date.issued	2013-07-18	de
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-0001-BACC-3	de
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-3944
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subject.ddc	610	de
dc.title	Influence of GPCR coexpression in neuronal cells on the convergence of signaling pathways	de
dc.type	doctoralThesis	de
dc.title.translated	Influence of GPCR coexpression in neuronal cells on the convergence of signaling pathways	de
dc.contributor.referee	Richter, Diethelm Prof. Dr.	de
dc.date.examination	2013-07-29	de
dc.description.abstracteng	Receptor crosstalk is a universal feature of signaling and interference happens on manifold pathway junctions. The physiological occurrence of the two serotonin receptor subtypes 5-HT1A and 5-HT7 in the same neuronal cells gave rise to the question of how their counter-cooperative impact merges on the mutual target adenylyl cyclase (AC). 5-HT1A receptors are generally known to decrease the cellular cAMP concentration via Gi mediated AC inhibition. In contrast, 5-HT7 receptors commonly increase [cAMP] via AC stimulating Gs proteins. Förster resonance energy transfer (FRET) measurements were performed in 5-HT1A – 5-HT7 coexpressing cells to track cAMP development during stimulation in real time. Fluorescent receptor labeling and visual selection of the measuring cells, combined with supporting FACS data and functional analysis ensured equal receptor expression in analyzed cells. An additional consideration is that many serotonin receptors, including 5-HT1A and 5-HT7, tend to oligomerize. Oligomerization has been shown to alter signaling in a vast number of cases and might play a key role in the 5-HT1A – 5-HT7 interaction. Coexpressing cells were stimulated with serotonin to examine what impact the common receptor expression had on [cAMP] and if one pathway appeared to be dominant. Subsequent specific inhibition of either receptor was supposed to review respective binding sites and further reveal the nature of 5-HT1A – 5-HT7 interaction. Blocking on the G protein level allowed analysis of the last step of the 5-HT pathway before the preliminary end target, AC. The key results of the actual thesis are summarized below: 1. Upon 5-HT1A – 5-HT7 coexpression a strong functional interaction with dominance of the Gi pathway became apparent. Coactivation of coexpressing cells leads to significant [cAMP] decrease. 2. Specific blockade of either receptor almost totally prevents 5-HT signaling in these cells. 3. Specific 5-HT7 stimulation likewise induces a [cAMP] decrease. Oligomerization of the two serotonin receptors might be a possible explanation for the newly observed signaling features. The available results cannot predict with certainty whether oligomerization occurs or not, but in any case a strong interaction became evident and gives rise to further investigation of serotonin receptor coexpression.	de
dc.contributor.coReferee	Nikolaev, Viacheslav Dr.	de
dc.subject.eng	5-HT1A	de
dc.subject.eng	5-HT7	de
dc.subject.eng	Receptor oligomerization	de
dc.subject.eng	Receptor crosstalk	de
dc.subject.eng	serotonin receptors	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-0001-BACC-3-9	de
dc.affiliation.institute	Medizinische Fakultät	de
dc.subject.gokfull	Physiologie / Pathophysiologie - Allgemein- und Gesamtdarstellungen (PPN619875283)	de
dc.description.embargoed	2013-08-05	de
dc.identifier.ppn	755375947	de

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