Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins: insight into mechanisms of G protein selectivity

Mobbs, Jesse I.; Belousoff, Matthew J.; Harikumar, Kaleeckal G.; Piper, Sarah; Xu, Xiaomeng; Furness, Sebastian G.B.; Venugopal, Hari; Christopoulos, Arthur; Danev, Radostin; Wootten, Denise; Thal, David M.; Miller, Laurence J.; Sexton, Patrick M.

doi:10.1101/2021.05.06.442871

Cited by 5 publications

(1 citation statement)

References 73 publications

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“…The receptors are found in the hippocampus, cerebral cortex, and striatum 12 . It's in the nuclei of solitary tracts and the lower area of the brain stem 13 . Tissue and development-specific CCK EPC expression are biphasic, falling just before delivery and rising immediately after 14 .…”

Section: Introductionmentioning

confidence: 99%

Investigation of Cholecystokinin-Beta receptor, IL-27, IL-27 gene SNP and some biochemical parameters in patients with Type-1 Diabetes Mellitus

AL-Musawi

Al-Gazally

AL-Saffar

2023

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Diabetes mellitus (DM) is a central public health problem impacting more than 400 million humhttp://wsx5customurl.comans worldwide. This metabolic disorder progressively drives chronic microvascular, macrovascular and neuropathic life-threatening problems. DM is happened because of a decrease in insulin secretion, harm to pancreatic β cells or insulin resistance connected to the nonuse of insulin. Type – I DM The immune system, by mistake, will attack the β cells of the pancreas, where genes play a vital role. The work was designed to determine the levels of anthropometric variables (age and BMI), immunological parameters (IL-27, IL-27 gene SNP), CCKBR and other biochemical parameters (HbA1C, cholesterol, triglyceride, HDL, LDL, VLDL, urea and creatinine) in sera of T1DM patients. The study contains 180 subjects who are split into two groups; the two groups are the healthy control group and the T1DM patients' group. The result recorded in this research showed a non-significant (p>0.05) difference between the control and patients in age, BMI, CCKBR, TRI, HDL, LDL, and VLDL. A very high significant elevation (P<0.001) has been observed in the level of IL-27, HbA1C, urea and creatinine; there is a highly significant increase (p<0.05) in cholesterol, the gene SNP study shows a significant association of IL27 rs153109 with T1DM was observed under the allele model (OR=2.124, 95% CI (1.349–3.345), P=0.00105), and genotype model in the dominant model (OR=1.00, 95% CI, P=0.0016), recessive model (OR=0.35, 95% CI ( 0.12–1.02), P=0.043) and homozygous model (OR=1.00, 95%, P=0.0037). The study it is cleared that T1DM affects the SNP gene used as a promoter to the excretion of IL-27 and increases its excretion. Lipid profile shows an effect on the level of glucose in the blood, and a high level of cholesterol may cause a severe problem if it is combined with T1DM. The elevated glucose level happens because T1DM affects the renal and causes extreme conditions like renal failure and other renal dysfunction diseases. Keywords: T1DM, CCKBR, genetic disease, IL-27, IL-27.

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Section: Introductionmentioning

confidence: 99%

Investigation of Cholecystokinin-Beta receptor, IL-27, IL-27 gene SNP and some biochemical parameters in patients with Type-1 Diabetes Mellitus

AL-Musawi

Al-Gazally

AL-Saffar

2023

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Molecular and structural insights into the 5‐HT_2C receptor as a therapeutic target for substance use disorders

Ubhayarathna,

Langmead,

Diepenhorst

et al. 2023

British J Pharmacology

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Substance use disorder (SUD) is a chronic condition with maintained abuse of a substance leading to physiological and psychological alterations and often changes in cognitive and social behaviours. Current therapies include psychotherapy coupled with medication; however, high relapse rates reveal the shortcomings of these therapies.The signalling, expression profile, and neurological function of the serotonin 2C receptor (5‐HT2C receptor) make it a candidate of interest for the treatment of SUD. Recently, psychedelics, which broadly act at 5‐HT2 receptors, have indicated potential for the treatment of SUD, implicating the 5‐HT2C receptor. The modern psychedelic movement has rekindled interest in the 5‐HT2C receptor, resulting in many new studies, especially structural analyses.This review explores the structural, molecular and cellular mechanisms governing 5‐HT2C receptor function, in the context of SUD. This provides the basis of the preclinical and clinical evidence for their role in SUD and highlights the potential for future exploration.

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Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues

et al. 2022

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All processes in human physiology relies on homeostatic mechanisms which require the activation of specific control circuits to adapt the changes imposed by external stimuli. One of the critical modulators of homeostatic balance is autophagy, a catabolic process that is responsible of the destruction of long-lived proteins and organelles through a lysosome degradative pathway. Identification of the mechanism underlying autophagic flux is considered of great importance as both protective and detrimental functions are linked with deregulated autophagy. At the mechanistic and regulatory levels, autophagy is activated in response to diverse stress conditions (food deprivation, hyperthermia and hypoxia), even a novel perspective highlight the potential role of physical forces in autophagy modulation. To understand the crosstalk between all these controlling mechanisms could give us new clues about the specific contribution of autophagy in a wide range of diseases including vascular disorders, inflammation and cancer. Of note, any homeostatic control critically depends in at least two additional and poorly studied interdependent components: a receptor and its downstream effectors. Addressing the selective receptors involved in autophagy regulation is an open question and represents a new area of research in this field. G-protein coupled receptors (GPCRs) represent one of the largest and druggable targets membrane receptor protein superfamily. By exerting their action through G proteins, GPCRs play fundamental roles in the control of cellular homeostasis. Novel studies have shown Gαq, a subunit of heterotrimeric G proteins, as a core modulator of mTORC1 and autophagy, suggesting a fundamental contribution of Gαq-coupled GPCRs mechanisms in the control of this homeostatic feedback loop. To address how GPCR-G proteins machinery integrates the response to different stresses including oxidative conditions and mechanical stimuli, could provide deeper insight into new signaling pathways and open potential and novel therapeutic strategies in the modulation of different pathological conditions.

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Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins: insight into mechanisms of G protein selectivity

Cited by 5 publications

References 73 publications

Investigation of Cholecystokinin-Beta receptor, IL-27, IL-27 gene SNP and some biochemical parameters in patients with Type-1 Diabetes Mellitus

Investigation of Cholecystokinin-Beta receptor, IL-27, IL-27 gene SNP and some biochemical parameters in patients with Type-1 Diabetes Mellitus

Molecular and structural insights into the 5‐HT_2C receptor as a therapeutic target for substance use disorders

Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues

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Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins: insight into mechanisms of G protein selectivity

Cited by 5 publications

References 73 publications

Investigation of Cholecystokinin-Beta receptor, IL-27, IL-27 gene SNP and some biochemical parameters in patients with Type-1 Diabetes Mellitus

Investigation of Cholecystokinin-Beta receptor, IL-27, IL-27 gene SNP and some biochemical parameters in patients with Type-1 Diabetes Mellitus

Molecular and structural insights into the 5‐HT2C receptor as a therapeutic target for substance use disorders

Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues

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Product

Resources

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Molecular and structural insights into the 5‐HT_2C receptor as a therapeutic target for substance use disorders