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<jats:title>ABSTRACT</jats:title><jats:p>The glucagon-like peptide-1 receptor (GLP1R) is a class B G protein-coupled receptor (GPCR) involved in metabolism. Presently, its visualization is limited to genetic manipulation, antibody detection or the use of probes that stimulate receptor activation. Herein, we present <jats:bold>LUXendin645</jats:bold>, a far-red fluorescent GLP1R antagonistic peptide label. <jats:bold>LUXendin645</jats:bold> produces intense and specific membrane labeling throughout live and fixed tissue. GLP1R signaling can additionally be evoked when the receptor is allosterically modulated in the presence of <jats:bold>LUXendin645</jats:bold>. Using <jats:bold>LUXendin645</jats:bold> and STED-compatible <jats:bold>LUXendin651</jats:bold> we describe islet GLP1R expression patterns, reveal higher-order GLP1R organization including the existence of membrane nanodomains, and track single receptor subpopulations. We furthermore show that different fluorophores can confer agonistic behavior on the <jats:bold>LUXendin</jats:bold> backbone, with implications for the design of stabilized incretin-mimetics. Thus, our labeling probes possess divergent activation modes, allow visualization of endogenous GLP1R, and provide new insight into class B GPCR distribution and dynamics.</jats:p>

Original publication

DOI

10.1101/557132

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

27/02/2019