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The role of SGIP1 protein interaction with cannabinoid receptor 1 in nociception under pathological conditions.
Dresslerová, Denisa ; Špicarová, Diana (advisor) ; Zímová, Lucie (referee)
The cannabinoid receptor type 1 (CB1) is a component of the endocannabinoid system and is abundantly expressed in the central nervous system. CB1 receptor has been extensively studied primarily due to its inhibitory role in neurotransmitter release from presynaptic terminals, and this process subsequently modulates postsynaptic currents and postsynaptic neuron excitation. Its interaction with the Src homology domain 3 growth factor 2 receptor binding protein (SGIP1) has recently been investigated in the context of nociception modulation (Hájková et al., 2016b). However, the role of this CB1 regulatory protein, SGIP1, in pathological pain conditions has not yet been described. Clarification of the role of SGIP1 interaction with CB1 receptor may help future research based on the use of cannabinoids as potential therapeutics. The thesis is structured into two parts, theoretical and practical. In the theoretical part of the thesis, knowledge of the given topic is summarized. First, pain is described from an anatomical-physiological perspective, followed by a description of the endocannabinoid system, where a part is dedicated to the CB1 cannabinoid receptor itself, and then another part is dedicated to the SGIP1 protein and its interaction with the CB1 receptor. In the practical part, the role of SGIP1...
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The role of regulatory protein SGIP1 in nociceptive synaptic transmission at the spinal cord level.
Mužík, David ; Špicarová, Diana (advisor) ; Lindovský, Jiří (referee)
Cannabinoid receptor 1 (CB1), abundantly expressed in the CNS, is a promising target for the pharmacological treatment of pathological pain conditions due to its function as an inhibitor of neurotransmitter release from presynaptic neurons. Recently, the SGIP1 protein has been found to interact with the CB1 receptor and participates in the modulation of nociception. However, whether SGIP1 modulates spinal CB1 receptor signaling at the spinal cord level is unknown. To answer this question, we used the patch-clamp method in the superficial spinal cord dorsal horn neurons of wild-type (WT) and knockout (KO) SGIP1 mice to measure spontaneous (s) and miniature (m) excitatory postsynaptic currents (EPSCs). Results of naive mice and mice with carrageenan-induced peripheral inflammation were compared. The results show that the efficacy of the CB1 receptor agonist WIN 55,212-2 at the first spinal nociceptive synapse is identical in naive mice for both SGIP1 WT and KO phenotypes. The control frequencies of both groups of neurons did not differ in naïve conditions or the peripheral inflammation model. On the contrary, the WIN 55,212-2 application was more effective in SGIP1 KO mice during peripheral inflammation. This study further addressed how CB1 receptor activation affects spinal inhibitory synaptic...
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Molecular mechanism of Cannabinoid receptor 1 regulation by SGIP1
Dvořáková, Michaela ; Blahoš, Jaroslav (advisor) ; Konvalinka, Jan (referee) ; Stuchlík, Aleš (referee)
Molecular mechanism of Cannabinoid receptor 1 regulation by SGIP1 Abstract 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...
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Influence of protein SGIP1 on partners participating in signalization of cannabinoid receptor 1
Pejšková, Lucie ; Blahoš, Jaroslav (advisor) ; Novotný, Jiří (referee)
The G-protein-coupled receptor (GPCR) family represents the largest family of cell surface receptors. GPCRs are activated by endogenous or exogenous ligands, and are targets for more than a quarter of currently used drugs. Activation of receptors initiates intracellular signaling pathways. This way the membrane receptors transfer information from the outside environment into the cell. Based on the signal the cell can respond to the changes of the environment. Key observation important for this thesis is interplay of cannabinoid and opioid signaling in vivo, which can have significant physiological effects1 . Cannabinoid receptor 1 (CB1R) and µ opioid receptor (MOR) belong to the rhodopsin family of receptors, and both are coupled with Gαi/o proteins2 . Both are located in certain areas in central nervous system (CNS) and share a lot of important features. Activation of both of the receptors leads to inhibition of adenylyl cyclase, thus decreasing the level of cyclic adenosine monophosphate in the cell, and modulates extracellular regulated kinase 1 and 2 (ERK1/2)2 . In view of the numerous anatomical, biochemical and pharmacological evidence supporting the existence of the functional interaction between opioid3 and cannabinoid receptor systems this topic became interesting for our research. In our...
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