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Role of Ca2+ and L-Phe in regulating functional cooperativity of disease-associated 'toggle' calcium-sensing receptor mutations.

التفاصيل البيبلوغرافية
العنوان: Role of Ca2+ and L-Phe in regulating functional cooperativity of disease-associated 'toggle' calcium-sensing receptor mutations.
المؤلفون: Chen Zhang, Nagaraju Mulpuri, Fadil M Hannan, M Andrew Nesbit, Rajesh V Thakker, Donald Hamelberg, Edward M Brown, Jenny J Yang
المصدر: PLoS ONE, Vol 9, Iss 11, p e113622 (2014)
بيانات النشر: Public Library of Science (PLoS), 2014.
سنة النشر: 2014
المجموعة: LCC:Medicine
LCC:Science
مصطلحات موضوعية: Medicine, Science
الوصف: The Ca(2+)-sensing receptor (CaSR) regulates Ca(2+) homeostasis in the body by monitoring extracellular levels of Ca(2+) ([Ca(2+)]o) and amino acids. Mutations at the hinge region of the N-terminal Venus flytrap domain (VFTD) produce either receptor inactivation (L173P, P221Q) or activation (L173F, P221L) related to hypercalcemic or hypocalcemic disorders. In this paper, we report that both L173P and P221Q markedly impair the functional positive cooperativity of the CaSR as reflected by [Ca(2+)]o-induced [Ca(2+)]i oscillations, inositol-1-phosphate (IP1) accumulation and extracellular signal-regulated kinases (ERK1/2) activity. In contrast, L173F and P221L show enhanced responsiveness of these three functional readouts to [Ca(2+)]o. Further analysis of the dynamics of the VFTD mutants using computational simulation studies supports disruption in the correlated motions in the loss-of-function CaSR mutants, while these motions are enhanced in the gain-of-function mutants. Wild type (WT) CaSR was modulated by L-Phe in a heterotropic positive cooperative way, achieving an EC50 similar to those of the two activating mutations. The response of the inactivating P221Q mutant to [Ca(2+)]o was partially rescued by L-Phe, illustrating the capacity of the L-Phe binding site to enhance the positive homotropic cooperativity of CaSR. L-Phe had no effect on the other inactivating mutant. Moreover, our results carried out both in silico and in intact cells indicate that residue Leu(173), which is close to residues that are part of the L-Phe-binding pocket, exhibited impaired heterotropic cooperativity in the presence of L-Phe. Thus, Pro(221) and Leu(173) are important for the positive homo- and heterotropic cooperative regulation elicited by agonist binding.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1932-6203
Relation: http://europepmc.org/articles/PMC4242666?pdf=render; https://doaj.org/toc/1932-6203
DOI: 10.1371/journal.pone.0113622
URL الوصول: https://doaj.org/article/4d37cc14efa74f3ba3cd8251071ff027
رقم الأكسشن: edsdoj.4d37cc14efa74f3ba3cd8251071ff027
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:19326203
DOI:10.1371/journal.pone.0113622