Conformational determinants in receptor recognition of peptide hormones: interaction of parathyroid hormone with the glucagon receptor.
Receptor binding assays demonstrate that bovine parathyroid hormone (PTH) and human PTH(1-34) can displace [125I]iodoglucagon from binding to its receptor in rat liver plasma membranes. The displacement of [125I]iodoglucagon requires several thousand-fold more bovine PTH or human PTH(1-34) than glucagon. However, the PTH peptides are more effective than secretin, which up to a concentration of 10(-5) M exhibits no ability to displace [125I]iodoglucagon. The greater potency of PTH compared with secretin occurs despite the fact that secretin shows a great deal of sequence homology with glucagon while PTH shows none. We demonstrate by circular dichroism that in the presence of 3 mM SDS glucagon and hPTH(1-34) have similar secondary structure contents, while secretin is more helical. Our results suggest that receptors can recognize gross conformational features of a peptide hormone in addition to interacting with a specific amino acid sequence. The ability of PTH to interact with glucagon receptors can be modulated by incorporation of charged amphiphiles into the plasma membrane. Negatively charged taurodeoxycholic acid increases the binding of the more cationic PTH while positively charged myristyltrimethylammonium bromide decreases this interaction. These effects demonstrate that receptor specificity can be modulated by its lipid environment and that electrostatic interactions between the hormone and the membrane surface can contribute to receptor binding.
D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D005934:Glucagon / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism*; D011487:Protein Conformation; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000187:drug effects / Q000378:metabolism*; D018027:Receptors, Glucagon; D012633:Secretin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013657:Taurodeoxycholic Acid / Q000494:pharmacology; D050337:Trimethyl Ammonium Compounds
D010281:Parathyroid Hormone; D000644:Quaternary Ammonium Compounds; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D050337:Trimethyl Ammonium Compounds; D012633:Secretin; D013657:Taurodeoxycholic Acid; D005934:Glucagon; C009410:tetradecyltrimethylammonium