Proposed models for the mode of action of GPCR-bigrams.

<p>In each model, agonist binding on the receptor domain leads to downstream responses. In (A), the catalytic domain (c) is directly activated, leading to conversion of a substrate (s) to a product (p). In (B), proteolytic cleavage (purple) yields a mature GPCR and an active catalytic domain. In (C), G-proteins are activated, which either directly or indirectly activate the catalytic domain. In (D), the catalytic domain is activated by G-proteins or effector proteins, activated by a canonical GPCR. In (E), the catalytic domain is inactive (grey), and instead, G-proteins are activated to induce the production of second messengers. In (F), the receptor displays biased agonism and either activates G-proteins (left) or the catalytic domain (right). In (G), phosphorylation of the GPCR (yellow circles) by kinase activity of GPCR-TKLs leads to recruitment of β-arrestin, thereby either blocking signaling via G-proteins (left) or scaffolding effector proteins to initiate downstream signaling (right). GPCR, G-protein coupled receptor; TKL, tyrosine kinase-like.