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Specific targeting of pancreatic β‐cells for imaging and therapy using multivalent targeting of receptor combinations
Author(s) -
Hart Nathaniel,
Vagner Josef,
Chung Woo Jin,
Weber Craig,
Limesand Sean,
Silva Channa,
Lynch Ronald
Publication year - 2012
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.26.1_supplement.1064.2
Subject(s) - receptor , chemistry , microbiology and biotechnology , ligand (biochemistry) , cell , biophysics , medicine , endocrinology , biology , biochemistry
Perturbations in pancreatic β‐cell mass (BCM) and function underlie the development of Diabetes Mellitus. Current treatments and analysis of BCM are limited by inadequate specificity of β‐cell targeting agents. We propose improved specificity of β‐cell agents can be obtained by targeting unique combinations of cell surface proteins that distinguish β‐cells from other cells within the abdomen. We synthesized a multivalent ligand composed of two different receptor binding moieties: Glucagon Like Peptide‐1 (GLP‐1) and Glibenclamide (Glb, Sulfonyurea ligand, SUR1). Both GLP1R and SUR1 are expressed in the βTC3 cell line. The bivalent ligand binds to βTC3 cells with an apparent K m of ~10nM, and binding is right‐shifted by competition with monomeric GLP‐1 or Glb, indicating higher affinity binding is due to multivalent interactions. GLP‐1 elevates cAMP while Glb increases Ca 2+ in β‐cells. We observe that the GLP‐1/Glb elicits a half maximal Ca 2+ response at ~10nM reflecting its K m but the magnitude of the Ca 2+ response was at least 10X less than monomeric Glb. Unlike the Ca 2+ response, cAMP production was depressed by only ~20% compared to monomeric GLP‐1. Although signaling is depressed, glucose activated insulin secretion is potentiated to similar levels by both monomeric GLP‐1 and GLP1/Glb. Our findings indicate that multivalent ligands may provide cell type specific agents with tunable functional behavior. Supported by Juvenile Diabetes Research Foundation.