Molecular mechanism of Cannabinoid receptor 1 regulation by SGIP1

• Název práce v češtině: Molekulární mechanismus regulace signalizace kanabinoidního receptoru 1 proteinem SGIP1
• Název v anglickém jazyce: Molecular mechanism of Cannabinoid receptor 1 regulation by SGIP1
• Klíčová slova: Autaptické hipokampální neurony, bolest, elektrofyziologie (metoda terčíkového zámku), endokanabinoidní systém, kanabinoidní receptor 1, receptor spojený s G proteinem, SGIP1, tolerance, úzkost
• Klíčová slova anglicky: Anxiety, autaptic hippocampal neurons, cannabinoid receptor 1, endocannabinoid system, G protein coupled receptor, pain, SGIP1, tolerance, whole-cell patch-clamp electrophysiology
• Akademický rok vypsání: 2014/2015
• Typ práce: disertační práce
• Jazyk práce: angličtina
• Ústav: Ústav farmakologie (13-311)
• Vedoucí / školitel: doc. MUDr. Jaroslav Blahoš, Ph.D.
• Řešitel: skrytý - zadáno a potvrzeno stud. odd.
• Datum přihlášení: 26.03.2015
• Datum zadání: 26.03.2015
• Datum potvrzení stud. oddělením: 26.03.2015
• Datum a čas obhajoby: 14.06.2021 14:00
• Datum odevzdání elektronické podoby: 26.03.2021
• Datum odevzdání tištěné podoby: 26.03.2021
• Datum proběhlé obhajoby: 14.06.2021
• Oponenti: prof. RNDr. Jan Konvalinka, CSc.

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Předběžná náplň práce

Src homology 3‐domain growth factor receptor‐bound 2‐like endophilin interacting protein 1 (SGIP1) byl identifikován jako interakční partner kanabinoidního receptoru 1 (CB1R). Jejich protein-proteinová interakce byla potvrzena koimunoprecipitací. SGIP1 brání internalizaci aktivovaného CB1R a moduluje jeho signalizaci v buňkách HEK293. Pomocí elektrofyziologické metody terčíkového zámku jsme prokázali, že SGIP1 ovlivňuje signalizaci CB1R v autaptických hipokampálních neuronech.
Sadou behaviorálních testů jsme zkoumali důsledky delece SGIP1 na chování regulované endokanabinoidním systémem u myší s konstitutivní delecí SGIP1 (SGIP1-/-) a myší WT. U myší SGIP1-/- nebylo změněno zkoumání prostředí, pracovní paměť a senzomotorické učení. Myši SGIP1-/- byly méně úzkostlivé a depresivní. U samic SGIP1-/- byla zrychlena extinkce averzivní vzpomínky. Projevy kanabinoidní tetrády byly delecí SGIP1 taktéž ovlivněny. Samci SGIP1-/- vykazovali abnormální příznaky závislosti na THC. Delece SGIP1 také snížila akutní nocicepci a myši SGIP1-/- byly citlivější na antinocicepční účinky agonistů CB1R a morfinu.
Interakce CB1R-SGIP1 vede k významné modifikaci signalizace CB1R. Pozorování in vivo dále naznačují, že SGIP1 ovlivňuje projevy chování souvisejícího s CB1R.

Předběžná náplň práce v anglickém jazyce

Src homology 3‐domain growth factor receptor‐bound 2‐like endophilin interacting protein 1 (SGIP1) has been identified as an interacting partner of cannabinoid receptor 1 (CB1R). Their protein-protein interaction was confirmed by co-immunoprecipitation. SGIP1 hinders the internalization of activated CB1R and modulates its signaling in HEK293 cells. Employing whole-cell patch-clamp electrophysiology, we have shown that SGIP1 affects CB1R signaling in autaptic hippocampal neurons.
Using a battery of behavioral tests in SGIP1 constitutive knock‐out (SGIP1‐/‐) and WT mice, we investigated the consequences of SGIP1 deletion on behavior regulated by the endocannabinoid system. In SGIP1‐/‐ mice, exploratory levels, working memory, and sensorimotor gating were unaltered. SGIP1‐/‐ mice showed decreased anxiety‐like and depressive-like behaviors. Fear extinction to tone was enhanced in SGIP1‐/‐ females. Several cannabinoid tetrad behaviors were altered in the absence of SGIP1. SGIP1‐/‐ males exhibited abnormal THC withdrawal behaviors. SGIP1 deletion also reduced acute nociception, and SGIP1‐/‐ mice were more sensitive to antinociceptive effects of CB1R agonists and morphine.
CB1R-SGIP1 interaction results in profound modification of CB1R signaling. Furthermore, in vivo findings suggest SGIP1 is a novel modulator of CB1R‐related behavior.