Adhesion GPCRs appear capable to follow standard GPCR signaling modes and signal through Gαs, Gαq, Gαi, and Gα12/13. As of today, many of the adhesion GPCRs are still orphan receptors and their signalling pathways have not been identified. Research groups are working to elucidate the downstream signaling molecules utilizing several methods, including chemical screens and analysis of second messenger levels in over-expressed cells. Adding drugs in vitro, while the cells are over-expressing an adhesion GPCR, has allowed the identification of the molecules activating the GPCR and the second messengers being utilized.
GPR133 signals through Gαs to activate adenylyl cyclase. It has been shown that overexpressing GPCRs in vitro can result in receptor activation in the absence of a ligand or agonist. By over expressing GPR133 in vitro, an elevation in reporter genes and cAMP was observed.  Signaling of the overexpressed GPR133 did not require an N-terminus or GPS cleavage.  Missense mutations in the 7TM region resulted in loss of signalling.
The latrophilin homolog LPHN1 was shown in C. elegans to require a GPS for signaling, but cleavage at the GPS site was not necessary. Furthermore, having a shortened 7 transmembrane domain, but with an intact GPS domain, resulted in a loss of signaling. This suggests that having both the GPS and 7 transmembrane domain intact is involved in signaling and that the GPS site could act as or be a necessary part of an endogenous ligand.
GPR56 has been shown to be cleaved at the GPS site and then remain associated with the 7TM domain.  In a study where the N-terminus was removed up to N342 (the start of the GPS), the receptor became constitutively active and an up regulation of Gα12/13 was seen.  When receptors are active, they are ubiquitinated and GPR56 lacking an N-terminus was highly ubiquitinated.