scholarly journals Roles of Cholecystokinin in the Nutritional Continuum. Physiology and Potential Therapeutics

2021 ◽  
Vol 12 ◽  
Author(s):  
Laurence J. Miller ◽  
Kaleeckal G. Harikumar ◽  
Denise Wootten ◽  
Patrick M. Sexton
Keyword(s):  
Peptide Hormone ◽  
Allosteric Modulators ◽  
Clinical Failure ◽  
Appetite Control ◽  
Positive Allosteric Modulator ◽  
Cholecystokinin Receptor ◽  
Metabolic Physiology ◽  
Treatment Of Obesity ◽  
Potential Therapeutics

Cholecystokinin is a gastrointestinal peptide hormone with important roles in metabolic physiology and the maintenance of normal nutritional status, as well as potential roles in the prevention and management of obesity, currently one of the dominant causes of direct or indirect morbidity and mortality. In this review, we discuss the roles of this hormone and its receptors in maintaining nutritional homeostasis, with a particular focus on appetite control. Targeting this action led to the development of full agonists of the type 1 cholecystokinin receptor that have so far failed in clinical trials for obesity. The possible reasons for clinical failure are discussed, along with alternative pharmacologic strategies to target this receptor for prevention and management of obesity, including development of biased agonists and allosteric modulators. Cellular cholesterol is a natural modulator of the type 1 cholecystokinin receptor, with elevated levels disrupting normal stimulus-activity coupling. The molecular basis for this is discussed, along with strategies to overcome this challenge with a corrective positive allosteric modulator. There remains substantial scope for development of drugs to target the type 1 cholecystokinin receptor with these new pharmacologic strategies and such drugs may provide new approaches for treatment of obesity.

scholarly journals Benzodiazepine ligands can act as allosteric modulators of the Type 1 cholecystokinin receptor

2008 ◽  
Vol 18 (15) ◽  
pp. 4401-4404 ◽  
Author(s):  
Fan Gao ◽  
Patrick M. Sexton ◽  
Arthur Christopoulos ◽  
Laurence J. Miller
Keyword(s):  
Allosteric Modulators ◽  
Cholecystokinin Receptor

scholarly journals Widespread Changes in Positive Allosteric Modulation of the Muscarinic M1 Receptor in Some Participants With Schizophrenia

2019 ◽  
Vol 22 (10) ◽  
pp. 640-650 ◽  
Author(s):  
Shaun Hopper ◽  
Geoffrey Mark Pavey ◽  
Andrea Gogos ◽  
Brian Dean
Keyword(s):  
Carboxylic Acid ◽  
Radioligand Binding ◽  
Allosteric Modulation ◽  
Allosteric Modulator ◽  
Allosteric Modulators ◽  
Positive Allosteric Modulator ◽  
M1 Receptor ◽  
Area 6 ◽  
Subcortical Regions

Abstract Background Preclinical and some human data suggest allosteric modulation of the muscarinic M1 receptor (CHRM1) is a promising approach for the treatment of schizophrenia. However, it is suggested there is a subgroup of participants with schizophrenia who have profound loss of cortical CHRM1 (MRDS). This raises the possibility that some participants with schizophrenia may not respond optimally to CHRM1 allosteric modulation. Here we describe a novel methodology to measure positive allosteric modulation of CHRM1 in human CNS and the measurement of that response in the cortex, hippocampus, and striatum from participants with MRDS, non-MRDS and controls. Methods The cortex (Brodmann’s area 6), hippocampus, and striatum from 40 participants with schizophrenia (20 MRDS and 20 non-MRDS) and 20 controls were used to measure benzyl quinolone carboxylic acid-mediated shift in acetylcholine displacement of [3H]N-methylscopolamine using a novel in situ radioligand binding with autoradiography methodology. Results Compared with controls, participants with schizophrenia had lower levels of specific [3H]N-methylscopolamine binding in all CNS regions, whilst benzyl quinolone carboxylic acid-modulated binding was less in the striatum, Brodmann’s area 6, dentate gyrus, and subiculum. When divided by subgroup, only in MRDS was there lower specific [3H]N-methylscopolamine binding and less benzyl quinolone carboxylic acid-modulated binding in all cortical and subcortical regions studied. Conclusions In a subgroup of participants with schizophrenia, there is a widespread decreased responsiveness to a positive allosteric modulator at the CHRM1. This finding may have ramifications it positive allosteric modulators of the CHRM1 are used in clinical trials to treat schizophrenia as some participants may not have an optimal response.

scholarly journals Ligand-induced internalization of the type 1 cholecystokinin receptor independent of recognized signaling activity

2012 ◽  
Vol 302 (3) ◽  
pp. C615-C627 ◽  
Author(s):  
Erin E. Cawston ◽  
Kaleeckal G. Harikumar ◽  
Laurence J. Miller
Keyword(s):  
Ligand Binding ◽  
Competitive Inhibition ◽  
Chinese Hamster ◽  
Receptor Internalization ◽  
Ovary Cell ◽  
Receptor Ligands ◽  
Cholecystokinin Receptor ◽  
Transmembrane Segments ◽  
Loop Region

Receptor ligands, identified as antagonists, based on the absence of stimulation of signaling, can rarely stimulate receptor internalization. d-Tyr-Gly-[(Nle28,31,d-Trp30)CCK-26–32]-2-phenylethyl ester (d-Trp-OPE) is such a ligand that binds to the cholecystokinin (CCK) receptor and stimulates internalization. Here, the molecular basis of this trafficking event is explored, with the assumption that ligand binding initiates conformational change, exposing an epitope to direct endocytosis. Ligand-stimulated internalization was studied morphologically using fluorescent CCK and d-Trp-OPE. d-Trp-OPE occupation of Chinese hamster ovary cell receptors stimulated internalization into the same region as CCK. Arrestin-biased action was ruled out using morphological translocation of fluorescent arrestin 2 and arrestin 3, moving to the membrane in response to CCK, but not d-Trp-OPE. Possible roles of the carboxyl terminus were studied using truncated receptor constructs, eliminating the proline-rich distal tail, the serine/threonine-rich midregion, and the remainder to the vicinal cysteines. None of these constructs disrupted d-Trp-OPE-stimulated internalization. Possible contributions of transmembrane segments were studied using competitive inhibition with peptides that also had no effect. Intracellular regions were studied with a similar strategy using coexpressing cell lines. Peptides corresponding to ends of each loop region were studied, with only the peptide at the carboxyl end of the third loop inhibiting d-Trp-OPE-stimulated internalization but having no effect on CCK-stimulated internalization. The region contributing to this effect was refined to peptide 309–323, located below the recognized G protein-association motif. While a receptor in which this segment was deleted did internalize in response to d-Trp-OPE, it exhibited abnormal ligand binding and did not signal in response to CCK, suggesting an abnormal conformation and possible mechanism of internalization distinct from that being studied. This interpretation was further supported by the inability of peptide 309–323 to inhibit its d-Trp-OPE-stimulated internalization. Thus the 309–323 region of the type 1 CCK receptor affects antagonist-stimulated internalization of this receptor, although its mechanism and interacting partner are not yet clear.

scholarly journals Molecular Basis of Action of a Small-Molecule Positive Allosteric Modulator Agonist at the Type 1 Cholecystokinin Holoreceptor

2018 ◽  
Vol 95 (3) ◽  
pp. 245-259 ◽  
Author(s):  
Aditya J. Desai ◽  
Ingrid Mechin ◽  
Karthigeyan Nagarajan ◽  
Celine Valant ◽  
Denise Wootten ◽  
...  
Keyword(s):  
Small Molecule ◽  
Molecular Basis ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator

scholarly journals Novel AT1R-Allosteric Ligands Mask the Preeclampsia Auto-antibody Epitope and Decrease Angiotensin-induced Vasoconstriction

2021 ◽  
Author(s):  
Khuraijam Dhanachandra Singh ◽  
Zaira P. Jara ◽  
Terri Harford ◽  
Prasenjit Prasad Saha ◽  
Triveni R. Pardhi ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Maternal Blood ◽  
Inhibitory Effect ◽  
Positive Allosteric Modulator ◽  
Small Molecule Screening ◽  
Dual Action ◽  
Auto Antibody ◽  
Loop 2 ◽  
Maternal Blood Pressure

SummaryMaternal blood pressure regulation by the hormone angiotensin II (AngII) sustains fetal growth through feto-placental circulation. AngII binding to orthosteric pocket in the angiotensin type 1 receptor (AT1R) induces G protein and β-arrestin signaling. AT1R blocking drugs and β-arrestin biased ligands also bind to the orthosteric pocket but evoke different inactive and active states1–6. AT1R-directed auto-antibodies observed in preeclampsia bound outside the orthosteric pocket to extracellular loop-2 (ECL2) of AT1R7–9. How auto-antibodies modulate AT1R activity causing preeclampsia pathogenesis is unknown. Here we report a druggable cryptic allosteric pocket encompassing the preeclampsia epitope on ECL2. Using structure based high-throughput small molecule screening we discovered 18 ligands specific for AT1R’s allosteric pocket. After procuring these ligands we validated inhibition of preeclampsia epitope-specific antibody binding. We characterize their inhibitory effect on antibody and AngII-signaling in cells and vasoconstriction ex vivo. These novel AT1R allosteric ligands, thus act as dual action negative modulators of auto-antibody action and vasoconstriction. Our study demonstrates that positive allosteric modulator action of auto-antibody causes a disease linked to AT1R. We anticipate our findings to kindle structure-based discovery of AT1R allosteric ligands for intervention in maladies such as preeclampsia7–10, rejection of organ transplants11, vasodilatory shock12, 13 and metabolic syndrome14.

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