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Pharmacology Futures 2018 – celebrating 250 years of pharmacology in Edinburgh
Sumoylation of the β2ARinfluences receptor internalisation, desensitisation and downstream signaling
Introduction: Beta 2 adrenergic receptor (β2AR) signalling can be modulated by a variety of post-translational modifications (PTMs) which include phosphorylation, ubiquitination, palmitoylation and glycosylation . Following sequence analysis of the β2AR, we discovered a putative site for SUMOylation, a previously unknown type of modification for this receptor. Our aim was to verify whether the β2AR can be SUMOylated and how this modification affects receptor signaling and desensitization.
Method: Using peptide array we have delineated a putative SUMO site on β2AR. Using both wild type and SUMO-null β2AR mutants we have investigated downstream signaling of the β2AR using western blotting. We have “forced” SUMOylation of the receptor via overexpression of the SUMO E3 ligase PIASy.
Results: We have identified a novel site of SUMOylation on the β2AR and shown that this modification robustly alters downstream signaling in a model cell-line. Specifically, we have demonstrated that SUMOylation reduces β2AR phosphorylation by PKA, altering the receptor driven phospho-ERK response, inhibits β2AR ubiquitination and degradation, and delays β2AR internalisation.
Conclusion: 10.0pt;We report for the first time that the β2AR can be SUMOylated and that this retards desensitization and receptor degradation. We speculate that this mechanism may be relevant to heart disease and have developed a β2AR SUMO-site specific antibody to investigate this possibility.
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