Abstract
In this review article, we summarize the current knowledge on a large and diverse superfamily of seven-pass transmembrane proteins functionally independent from the GPCR superfamily. We include the newest research findings about their physiological roles and their mechanism of action. In particular, we concentrate on the structural basis for the newly discovered amide hydrolase activity, with a focus on adiponectin receptors for which structures are available. Finally, we discuss the remaining challenges in understanding the activation and signaling of these intramembrane proteins and suggest how regulation of the amide hydrolase activity may help in development of new therapeutic agents.