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Differential Protein‐Protein Interactions Driven by the Arg/Gly389 Single Nucleotide Polymorphisms in the Cardiac Beta‐1 Adrenergic Receptor
Author(s) -
Bloomfield Christina,
Tran Quang-Kim
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09636
Subject(s) - calmodulin , snp , calcium , receptor , single nucleotide polymorphism , chemistry , adrenergic receptor , medicine , biophysics , biology , endocrinology , biochemistry , gene , genotype
Activation of the β1 adrenergic receptor (β 1 AR) increases electrically induced calcium signals and accelerates sequestration of calcium in the myocardium, promoting contraction and relaxation. In humans, Arg389 and Gly389 are common single nucleotide polymorphisms (SNPs) in β 1 AR. The Arg389 SNP is associated with higher responses to β agonists in terms of cAMP production and contractile force development; in living subjects, it also is coupled with faster response to b blockers with respect to reductions in heart rate and myocardial contractile force. Nevertheless, it is unknown if calcium signals following β 1 AR activation affects the receptor’s activities and changes in Ca 2+ ‐dependent regulation of β 1 AR can explain the difference between these polymorphisms. Calmodulin is the ubiquitous transducer of calcium signals and is a limiting factor in cardiomyocytes. We tested the hypothesis that β 1 AR directly interacts with calmodulin and that the Arg389 and Gly389 SNPs are associated with disparate β 1 AR‐calmodulin interactions. Using novel fluorescent biosensors developed for β 1 AR, we identified a novel calmodulin‐binding domain located at the juxtamembranous region of β 1 AR that encompasses the Arg/Gly389 SNP. The Arg389 SNP is associated with a biphasic interaction with Ca 2+ /calmodulin. However, the Gly389 SNP is associated with a monophasic interaction with CaM and a ~12‐fold lower affinity than the Arg389 SNP. These kinetic differences correspond to significant variances in the response of β 1 AR to physiological calmodulin concentrations, peaking at ~50 nM. We also identified that β 1 AR‐calmodulin interactions are calcium‐dependent, with higher Ca 2+ sensitivity of the Arg389 β 1 AR–CaM interaction over the entire physiological Ca 2+ range. These results suggest that calmodulin binding to β 1 AR is important for its functions and our observed different biochemical properties of these interactions may explain the different responses in subjects carrying the Arg389 vs the Gly389 SNPs. Support or Funding Information IOER grant 091707 to Q‐KT.