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Molecular aspects of vasopressin receptor function
T Schöneberg1, E Kostenis, J Liu
1Laboratory of Bioorganic Chemistry, NIH-NIDDK, Bethesda, Maryland 20892, USA.
Advances in Experimental Medicine and Biology
|February 23, 1999
Summary
Researchers identified key receptor regions for G protein coupling, crucial for vasopressin receptor function. A V2 receptor fragment rescued mutant receptors, suggesting a novel therapeutic strategy for genetic diseases.
Area of Science:
- Molecular pharmacology
- G protein-coupled receptors
- Molecular genetics
Background:
- Vasopressin receptors (V1a, V1b, V2) exhibit distinct G protein coupling preferences: V1a/V1b with Gq/11 and V2 with Gs.
- Intracellular loops are critical determinants of receptor-G protein interaction specificity.
Purpose of the Study:
- To elucidate the molecular mechanisms of G protein coupling selectivity within the vasopressin receptor family.
- To investigate the potential therapeutic application of a V2 receptor fragment for treating X-linked nephrogenic diabetes insipidus.
Main Methods:
- Combined molecular genetic and biochemical approaches, including functional analysis of V1a/V2 hybrid receptors.
- Coexpression of wild-type V1a receptors with chimeric G protein alpha subunits to identify critical residues.
- Rescue of mutant V2 vasopressin receptors using a C-terminal V2 receptor fragment (V2-tail) in cell lines and adenovirus-mediated gene transfer.
Main Results:
- The second intracellular loop of V1a and the third intracellular loop of V2 are sufficient for their respective G protein coupling.
- Two C-terminal residues of G protein alpha q/11 were identified as critical for V1a receptor recognition.
- A V2-tail fragment directly interacted with and functionally rescued mutant V2 receptors in cell lines.
- Adenovirus-mediated delivery of the V2-tail restored arginine vasopressin (AVP)-stimulated cAMP production in cells expressing mutant V2 receptors.
Conclusions:
- Specific intracellular loops dictate vasopressin receptor G protein coupling selectivity.
- Targeted expression of receptor fragments, like the V2-tail, offers a potential therapeutic strategy for genetic disorders caused by inactivating mutations in G protein-coupled receptors.