Beschreibung:
<jats:sec><jats:label /><jats:p>Activation of the β1 adrenergic receptor (β<jats:sub>1</jats:sub>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<jats:sub>1</jats:sub>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<jats:sub>1</jats:sub>AR activation affects the receptor’s activities and changes in Ca<jats:sup>2+</jats:sup>‐dependent regulation of β<jats:sub>1</jats:sub>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<jats:sub>1</jats:sub>AR directly interacts with calmodulin and that the Arg389 and Gly389 SNPs are associated with disparate β<jats:sub>1</jats:sub>AR‐calmodulin interactions. Using novel fluorescent biosensors developed for β<jats:sub>1</jats:sub>AR, we identified a novel calmodulin‐binding domain located at the juxtamembranous region of β<jats:sub>1</jats:sub>AR that encompasses the Arg/Gly389 SNP. The Arg389 SNP is associated with a biphasic interaction with Ca<jats:sup>2+</jats:sup>/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<jats:sub>1</jats:sub>AR to physiological calmodulin concentrations, peaking at ~50 nM. We also identified that β<jats:sub>1</jats:sub>AR‐calmodulin interactions are calcium‐dependent, with higher Ca<jats:sup>2+</jats:sup> sensitivity of the Arg389 β<jats:sub>1</jats:sub>AR–CaM interaction over the entire physiological Ca<jats:sup>2+</jats:sup> range. These results suggest that calmodulin binding to β<jats:sub>1</jats:sub>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.</jats:p></jats:sec><jats:sec><jats:title>Support or Funding Information</jats:title><jats:p>IOER grant 091707 to Q‐KT.</jats:p></jats:sec>