A Type 1 Cholecystokinin Receptor Mutant That Mimics the Dysfunction Observed for Wild Type Receptor in a High Cholesterol Environment

Desai, Aditya J.; Harikumar, Kaleeckal G.; Miller, Laurence J.

doi:10.1074/jbc.m114.570200

Cited by 21 publications

(51 citation statements)

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“…The CCK1R has been shown to be particularly sensitive to the cholesterol composition of the lipid bilayer [50, 51]. Membrane cholesterol elevated to levels reported in metabolic syndrome [52, 53], result in functional uncoupling of CCK binding from CCK-stimulated biological activity [50, 54–56]. In contrast, the closely-related CCK2R is not sensitive to this lipid [55, 56].…”

Section: Allosteric Modulation Of Endogenous Agonist Actionmentioning

confidence: 99%

“…Membrane cholesterol elevated to levels reported in metabolic syndrome [52, 53], result in functional uncoupling of CCK binding from CCK-stimulated biological activity [50, 54–56]. In contrast, the closely-related CCK2R is not sensitive to this lipid [55, 56]. This functional difference for structurally-related GPCRs that bind and are activated by CCK with similar high affinity and potency is an ideal setting to utilize chimeric CCK1R/CCK2R constructs to explore the molecular basis for this difference.…”

Section: Allosteric Modulation Of Endogenous Agonist Actionmentioning

confidence: 99%

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Metabolic Actions of the Type 1 Cholecystokinin Receptor: Its Potential as a Therapeutic Target

Miller

Desai

2016

Trends in Endocrinology & Metabolism

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Cholecystokinin regulates appetite and reduces food intake by activating the type 1 CCK receptor (CCK1R). Attempts to develop CCK1R agonists for obesity have yielded active agents that have not reached clinical practice. In this review we discuss why, along with new strategies to target CCK1R more effectively. We examine signaling events and the possibility of developing agents that exhibit ligand-directed bias, to dissociate satiety activity from undesirable side effects. Potential allosteric sites of modulation are also reviewed, along with desired properties of a positive allosteric modulator without intrinsic agonist action as another strategy to treat obesity. These new types of CCK1R-active drugs could be useful as stand-alone agents or as part of a rational drug combination for management of obesity.

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Section: Allosteric Modulation Of Endogenous Agonist Actionmentioning

confidence: 99%

Section: Allosteric Modulation Of Endogenous Agonist Actionmentioning

confidence: 99%

Metabolic Actions of the Type 1 Cholecystokinin Receptor: Its Potential as a Therapeutic Target

Miller

Desai

2016

Trends in Endocrinology & Metabolism

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“…55,56 In these studies, the impact of the cholesterol was reproduced, with elevated cholesterol resulting in higher-affinity CCK binding and lower signaling responsiveness to CCK (Figure 1). 56 This was shown to be specific to the CCK1R, with the CCK2R being resistant to the deleterious effects of cholesterol.…”

Section: Impact Of Membrane Cholesterol On Cck1r Structure and Functionmentioning

confidence: 99%

“…Indeed, this was done and it showed that this pocket was in a different conformation than either the agonist or antagonist pockets in a normal membrane. 55 This raised the extremely interesting possibility that unique drugs would have to be developed for this situation.…”

Section: Impact Of Membrane Cholesterol On Cck1r Structure and Functionmentioning

confidence: 99%

“…57 In addition, a CCK1R mutant affecting a residue at the bottom of TM3, near the DRY ionic lock mechanism and involving a cholesterol-binding motif, was shown to have all of the structural and functional effects typical of the wild-type CCK1R in a high-cholesterol environment. 55 This turned out to be a very powerful new tool. It could be used in analogous approaches to that used to characterize the allosteric pocket in agonist and antagonist modes, to try to characterize the abnormal pocket in the setting of elevated membrane cholesterol.…”

Section: Impact Of Membrane Cholesterol On Cck1r Structure and Functionmentioning

confidence: 99%

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Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

et al. 2016

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The gastrointestinal (GI) tract has a central role in nutritional homeostasis, as location for food ingestion, digestion and absorption, with the gut endocrine system responding to and regulating these events, as well as influencing appetite. One key GI hormone with the full spectrum of these activities is cholecystokinin (CCK), a peptide released from neuroendocrine I cells scattered through the proximal intestine in response to fat and protein, with effects to stimulate gall bladder contraction and pancreatic exocrine secretion, to regulate gastric emptying and intestinal transit, and to induce satiety. There has been interest in targeting the type 1 CCK receptor (CCK1R) for drug development to provide non-caloric satiation as an aid to dieting and weight loss; however, there have been concerns about CCK1R agonists related to side effects and potential trophic impact on the pancreas. A positive allosteric modulator (PAM) of CCK action at this receptor without intrinsic agonist activity could provide a safer and more effective approach to long-term administration. In addition, CCK1R stimulus-activity coupling has been shown to be negatively affected by excess membrane cholesterol, a condition described in the metabolic syndrome, thereby potentially interfering with an important servomechanism regulating appetite. A PAM targeting this receptor could also potentially correct the negative impact of cholesterol on CCK1R function. We will review the molecular basis for binding natural peptide agonist, binding and action of small molecules within the allosteric pocket, and the impact of cholesterol. Novel strategies for taking advantage of this receptor for the prevention and management of obesity will be reviewed.International Journal of Obesity Supplements (2016) 6, S22-S27; doi:10.1038/ijosup.2016.5 INTRODUCTIONThe prevalence of obesity has been progressively increasing throughout the United States and around the world, contributing to a parallel increase in the prevalence of type 2 diabetes mellitus and its associated comorbidities. 1 These problems have been responsible for extraordinary morbidity, suffering, loss in productivity and premature mortality. In spite of major efforts to develop effective weight reduction diets, diet aids, medications, medical devices and surgical procedures, the trajectory for this continues in the wrong direction. Bariatric surgery has proven to be quite effective in patients with morbid obesity; 2 however, this is quite expensive and not scalable, certainly not keeping up with the increasing prevalence of the most severe end of this clinical continuum. The activity of acute dieting and exercise has been similarly effective in inducing weight loss; however, it has not been durable, with an extremely high incidence of regaining weight to or even beyond the starting point. After a long hiatus in approved drugs, three new diet medications have recently been approved, 3-5 but all carry concerns about safety, and there are requirements for registration and careful clinical follow-up, re...

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Biased μ-opioid receptor agonists diversely regulate lateral mobility and functional coupling of the receptor to its cognate G proteins

Melkes

Hejnova

Novotný

2016

Naunyn-Schmiedeberg's Arch Pharmacol

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There are some indications that biased μ-opioid ligands may diversely affect μ-opioid receptor (MOR) properties. Here, we used confocal fluorescence recovery after photobleaching (FRAP) to study the regulation by different MOR agonists of receptor movement within the plasma membrane of HEK293 cells stably expressing a functional yellow fluorescent protein (YFP)-tagged μ-opioid receptor (MOR-YFP). We found that the lateral mobility of MOR-YFP was increased by (D-Ala,N-MePhe,Gly-ol)-enkephalin (DAMGO) and to a lesser extent also by morphine but decreased by endomorphin-2. Interestingly, cholesterol depletion strongly enhanced the ability of morphine to elevate receptor mobility but significantly reduced or even eliminated the effect of DAMGO and endomorphin-2, respectively. Moreover, the ability of DAMGO and endomorphin-2 to influence MOR-YFP movement was diminished by pertussis toxin treatment. The results obtained by agonist-stimulated [S]GTPγS binding assays indicated that DAMGO exhibited higher efficacy than morphine and endomorphin-2 did and that the efficacy of DAMGO, contrary to the latter agonists, was enhanced by cholesterol depletion. Overall, our study provides clear evidence that biased MOR agonists diversely affect receptor mobility in plasma membranes as well as MOR/G protein coupling and that the regulatory effect of different ligands depends on the membrane cholesterol content. These findings help to delineate the fundamental properties of MOR regarding their interaction with biased MOR ligands and cognate G proteins.

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A Type 1 Cholecystokinin Receptor Mutant That Mimics the Dysfunction Observed for Wild Type Receptor in a High Cholesterol Environment

Cited by 21 publications

References 56 publications

Metabolic Actions of the Type 1 Cholecystokinin Receptor: Its Potential as a Therapeutic Target

Metabolic Actions of the Type 1 Cholecystokinin Receptor: Its Potential as a Therapeutic Target

Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

Biased μ-opioid receptor agonists diversely regulate lateral mobility and functional coupling of the receptor to its cognate G proteins

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