7TM receptors are called GPCRs because they require interaction with heterotrimeric G proteins to signal. In humans the family of GPCRs is comprised of more than 800 members. Despite their large number, GPCRs share high sequence homology and rely on an amazingly small assortment of accessory molecules to regulate their ability to signal. One such regulatory protein family is the family of G protein-coupled receptor kinases (GRK), which consists of seven isoforms. GRKs provide the rate limiting mechanism for terminating incoming signals at the receptor to protect the cell from over-stimulation. Phosphorylation of the activated GPCR by GRKs is a prerequisite that not only commits the receptor to desensitize (separation from G protein) but also directs its association with a group of adaptor proteins termed arrestins and with the internalization machinery. The E/DRY (glutamic acid/aspartic acid, arginine, tyrosine) motif located at the end of the third transmembrane helix of GPCRs has been shown to be of particular importance for the execution of G protein-dependent signaling: Selective mutation of the R evidently triggers not only hyperphosphorylation by GRKs, but also the uncoupling of the G protein. Such mutated receptors constitutively associate with beta-arrestin and are localized to endosomal compartments.Zebrafish harboring a point mutation in the E/DRY motif of the 7TM sphingosine 1 phosphate receptor 2 (S1P2) develop a cardia bifida, a detrimental defect seen in heart development as it is characterized by the formation of two heart cylinders instead of one. We assume that the R150H point mutation of S1P2 results in a GPCR that is unresponsive to its ligand and constitutively inactive. Thus, the aim of this study is to investigate, if the cardiac phenotype of these embryos is caused by constitutive desensitization of S1P2 (R150H) and if it could be rescued by inhibiting GRKs and beta-arrestins, which spatially separate the receptor from its G protein.