JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
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Calcium modulates calmodulin/α-actinin 1 interaction with and agonist-dependent internalization of the adenosine A 2A receptor.

Adenosine receptors are G protein-coupled receptors that sense extracellular adenosine to transmit intracellular signals. One of the four adenosine receptor subtypes, the adenosine A2A receptor (A2A R), has an exceptionally long intracellular C terminus (A2A R-ct) that mediates interactions with a large array of proteins, including calmodulin and α-actinin. Here, we aimed to ascertain the α-actinin 1/calmodulin interplay whilst binding to A2A R and the role of Ca2+ in this process. First, we studied the A2A R-α-actinin 1 interaction by means of native polyacrylamide gel electrophoresis, isothermal titration calorimetry, and surface plasmon resonance, using purified recombinant proteins. α-Actinin 1 binds the A2A R-ct through its distal calmodulin-like domain in a Ca2+ -independent manner with a dissociation constant of 5-12μM, thus showing an ~100 times lower affinity compared to the A2A R-calmodulin/Ca2+ complex. Importantly, calmodulin displaced α-actinin 1 from the A2A R-ct in a Ca2+ -dependent fashion, disrupting the A2A R-α-actinin 1 complex. Finally, we assessed the impact of Ca2+ on A2A R internalization in living cells, a function operated by the A2A R-α-actinin 1 complex. Interestingly, while Ca2+ influx did not affect constitutive A2A R endocytosis, it abolished agonist-dependent internalization. In addition, we demonstrated that the A2A R/α-actinin interaction plays a pivotal role in receptor internalization and function. Overall, our results suggest that the interplay of A2A R with calmodulin and α-actinin 1 is fine-tuned by Ca2+ , a fact that might power agonist-mediated receptor internalization and function.

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