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Complexes of secretin (SecR) and angiotensin 1a (Atr1a) receptors have been proposed to be functionally important in osmoregulation, providing an explanation for overlapping and interdependent functions of hormones that bind and activate different classes of GPCRs. However, the nature of these crossclass complexes has not been well characterized and their signaling properties have not been systematically explored. We now use competitive inhibition of receptor bioluminescence resonance energy transfer and bimolecular fluorescence complementation to establish the dominant functionally important state as a symmetrical homodimeric form of SecR decorated by monomeric Atr1a, interacting through lipid-exposed faces of Atr1a TM1 and TM4. Conditions increasing prevalence of this complex exhibited negative allosteric modulatory impact on secretin-stimulated cAMP responses at SecR. In contrast, activating Atr1a with full agonist in such a complex exhibited a positive allosteric modulatory impact on the same signaling event. This modulation was functionally biased, with secretin-stimulated calcium responses unaffected, whereas angiotensin-stimulated calcium responses through the complex were reduced or absent. Further supporting this interpretation, Atr1a with mutations of lipid-exposed faces of TM1 and TM4 that did not affect its ability to bind or signal, could be expressed in the same cell as SecR, yet not exhibit either the negative or positive allosteric impact on cAMP observed with the inactive or activated states of wild type Atr1a on function, and not interfere with angiotensin-stimulated calcium responses like complexes with Atr1a. This may provide a more selective means of exploring the physiologic functional impact of this cross-class receptor complex without interfering with the function of either component receptor. [ABSTRACT FROM AUTHOR]

Body fluid homeostasis is critical for the survival of living organisms and hence is tightly controlled. From initial studies on the effects of secretin (SCT) on renal water reabsorption in the 1940s and recent investigations of its role in cardiovascular and neuroendocrine functions, it has now become increasingly clear that this peptide is an integral component of the homeostatic processes that maintain body fluid balance. This review, containing some of our recent findings of centrally expressed SCT on water intake, focuses on the actions of SCT in influencing the physiological, neuroendocrine, and cardiovascular processes that subserve body fluid homeostasis. [ABSTRACT FROM AUTHOR]