Meeting Abstract

87.7  Thursday, Jan. 7  Molecular Evolution of Mineralocorticoid Receptor – Hormone Interactions BRIDGHAM, J.T.*; ORTLUND, E.A.; THORNTON, J.W.; Univ. of Oregon, Eugene; Emory University School of Medicine, Atlanta, GA; Howard Hughes Medical Institute, Univ. of Oregon, Eugene jamieb@uoregon.edu

Mineralocorticoid receptors (MRs) in mammals are activated by the hormone aldosterone whereas MRs of teleosts are activated by deoxycorticosterone. In order to examine the evolution of these specific interactions between MRs and their hormones, we use a combination of techniques of molecular endocrinology, phylogenetics, and crystallography. We first characterize receptors isolated from extant species, and use molecular phylogenetic techniques to infer the sequences of ancestral receptors of the MRs, then resurrect and functionally characterize these ancestral receptors. Our results reveal a promiscuous ancient receptor that was activated by the mineralocorticoids aldosterone and deoxycorticosterone as well as cortisol. The MR-aldosterone partnership therefore evolved through a process of molecular exploitation, where the structure of the receptor was already capable of being activated by aldosterone before the enzymes to produce this hormone evolved. By characterizing MRs from multiple vertebrate species including agnathans, elasmobranchs, teleosts and tetrapods, we show that MRs lost activation by deoxycorticosterone and cortisol and became more specific for aldosterone once the enzymes to synthesize the hormone evolved.