Molecular basis of association of receptor activity-modifying protein 3 with the family B G protein-coupled secretin receptor

The three receptor activity-modifying proteins (RAMPs) have been recognized as being important for the trafficking and function of a subset of family B G protein-coupled receptors, although the structural basis for this has not been well established. In the current work, we use morphological fluorescence techniques, bioluminescence resonance energy transfer, and bimolecular fluorescence complementation to demonstrate that the secretin receptor associates specifically with RAMP3, but not with RAMP1 or RAMP2. We use truncation constructs, peptide competition experiments, and chimeric secretin-GLP1 receptor constructs to establish that this association is structurally specific, dependent on the intramembranous region of the RAMP and TM6 and TM7 of this receptor. There were no observed changes in secretin-stimulated cAMP, intracellular calcium, ERK1/2 phosphorylation, or receptor internalization in receptor-bearing COS or CHO-K1 cells in the presence or absence of exogenous RAMP transfection, although the secretin receptor trafficks normally to the cell surface in these cells in a RAMP-independent manner, resulting in both free and RAMP-associated receptor on the cell surface. RAMP3 association with this receptor was shown to be capable of rescuing a receptor mutant (G241C) that is normally trapped intracellularly in the biosynthetic machinery. Similarly, secretin receptor expression had functional effects on adrenomedullin activity, with increasing secretin receptor expression competing for RAMP3 association with the calcitonin receptor-like receptor to yield a functional adrenomedullin receptor. These data provide important new insights into the structural basis for RAMP3 interaction with a family B G protein-coupled receptor, potentially providing a highly selective target for drug action. This may be representative of similar interactions between other members of this receptor family and RAMP proteins

Progesterone receptors mediate male aggression toward infants

Neuroendocrine mechanisms that mediate male aggression toward infants are poorly understood. Although testosterone is known to enhance aggression in other social contexts, evidence that it modulates aggression toward infants is equivocal. We have found that male progesterone receptor knockout (PRKO) mice exhibit no infanticidal behavior and little aggression toward young. Male PRKO mice also display significantly enhanced parental behaviors. In wild-type mice, blockade of PR induces a behavioral phenotype similar to that of the PRKO males, whereas progesterone exacerbates aggressive tendencies toward infants. Aggressive behaviors directed toward adult males, by contrast, are unaffected by progesterone, PR antagonism, or PR gene deletion. Previously thought to be of diminished importance in male animals, PRs play a critical and specific role in modulating infant-directed behaviors in male mice