Insights learned from L457(3.43)R, an activating mutant of the human lutropin receptor

Ana Claudia Latronico; Deborah L Segaloff

doi:10.1016/j.mce.2005.11.053

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Insights learned from L457(3.43)R, an activating mutant of the human lutropin receptor

Journal article

Peer reviewed

Insights learned from L457(3.43)R, an activating mutant of the human lutropin receptor

Ana Claudia Latronico and Deborah L Segaloff

Molecular and cellular endocrinology, Vol.260-262, pp.287-293

01/02/2007

DOI: 10.1016/j.mce.2005.11.053

PMCID: PMC1785107

PMID: 17055147

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https://www.ncbi.nlm.nih.gov/pmc/articles/1785107View

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Abstract

The L457(3.43)R mutation of the hLHR was initially identified in a Brazilian boy with gonadotropin-independent precocious puberty. As would be expected, L457(3.43)R, when expressed in 293cells, caused a marked elevation in basal cAMP levels. Interestingly, in spite of the fact that the elevated basal levels of cAMP elicited by L457R were not as great as those elicited by the wild-type hLHR when stimulated with hCG, L457(3.43)R cells were unresponsive to further hormonal stimulation. We have since determined that the L457(3.43)R mutant, as well as other constitutively active mutants of the hLHR, causes an increase in phosphodiesterase activity that attenuates the target cell to hormonal stimulation of the wild-type hLHR or other Gs-coupled GPCRs. We have also shown that the constitutive activity and lack of hormonal responsiveness of L457(3.43)R are due to the formation of a salt bridge between the introduced arginine in the mid portion of helix 3 with D578(6.44) in the mid portion of helix 6. The formation of this salt bridge results in the disruption of interactions between the cytoplasmic ends of helices 3 and 6 that are associated in general with activation of the hLHR. As such, this mutant has provided novel insights into the properties of target cells expressing activating hLHR mutants and into the structural basis for hLHR activation.

G protein-coupled receptor (GPCR)

Constitutive activation

Constitutively active mutant

Lutropin receptor (LH receptor)

Details

Title: Subtitle: Insights learned from L457(3.43)R, an activating mutant of the human lutropin receptor
Creators: Ana Claudia Latronico - Developmental Endocrinology Unit, Hormone and Molecular Genetics Laboratory, Clinical Hospital, Sao Paulo University Medical School, Sao Paulo, Brazil
Deborah L Segaloff - Department of Physiology and Biophysics, The Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52246, USA
Resource Type: Journal article
Publication Details: Molecular and cellular endocrinology, Vol.260-262, pp.287-293
DOI: 10.1016/j.mce.2005.11.053
PMID: 17055147
PMCID: PMC1785107
NLM abbreviation: Mol Cell Endocrinol
ISSN: 0303-7207
eISSN: 1872-8057
Publisher: Elsevier Ireland Ltd
Language: English
Date published: 01/02/2007
Academic Unit: Molecular Physiology and Biophysics; Obstetrics and Gynecology
Record Identifier: 9984083239202771

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