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Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
GHS-R1a constitutive activity and its physiological relevance
Yves Mear1, Alain Enjalbert, Sylvie Thirion
1CNRS, CRN2M UMR7286, Aix Marseille University Marseille, France.
Frontiers in Neuroscience
|June 12, 2013
Summary
Ghrelin receptor (GHS-R1a) constitutive activity influences physiological functions like growth hormone secretion and body weight. Targeting this activity with inverse agonists may offer future therapeutic benefits.
Area of Science:
- Endocrinology
- Molecular Pharmacology
- Physiology
Background:
- Ghrelin binding to GHS-R1a is crucial for physiological functions.
- GHS-R1a exhibits high constitutive activity, impacting downstream signaling.
- Understanding GHS-R1a constitutive activity is key to its physiological roles.
Purpose of the Study:
- To review evidence on GHS-R1a constitutive activity.
- To explore the mechanisms underlying GHS-R1a constitutive activity.
- To discuss the implications of GHS-R1a constitutive activity in physiological impairments.
Main Methods:
- Literature review of recent evidence.
- Analysis of ligand-binding pocket interactions.
- Examination of signaling pathway activation (PLC, PKC, CRE).
- Investigation of GHS-R1a internalization and mutation effects.
Main Results:
- Ligand-binding pocket TM domains and ECL2 interaction contribute to constitutive activity.
- Constitutive activity activates PLC, PKC, and CRE pathways, reversible by inverse agonists.
- C-terminal dependent internalization of GHS-R1a observed.
- A specific mutation (Ala204Glu) linked to familial short stature exclusively affects constitutive activity.
Conclusions:
- GHS-R1a constitutive activity plays a role in growth hormone secretion and body weight regulation.
- The Ala204Glu mutation highlights the clinical relevance of constitutive activity.
- Further research into GHS-R1a inverse agonists holds significant clinical potential.
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