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terminus contains a cysteine-rich domain (CRD) that binds calcium levels in a G-protein-dependent manner either dir-Review TRENDS in Pharmacological Sciences Vol.28 No.10the receptor’s cognate ligands, which are proteins of the WNT family of lipoglycoproteins [3,4]. Amino acid hydropa-thy analysis predicts a conventional 7TM structure contain-ing one extracellular N terminus, three extra- and three intracellular loops and an intracellular C terminus. Putative glycosylation sites on the extracellular loops of FZD could be involved in ligand binding and have been shown to be important in the endoplasmic reticulum for receptormaturation,which is regulated ina specificmanner by the protein Shisa [5]. Sequence and mutational analyses revealed the presence of an internal C-terminal PDZ (PSD-95/dics large/ZO-1 homologous)-binding domain, pro-viding a protein-interacting interface for the receptor. ectly, through activation of phospholipases [9], or indirectly, via a decrease in intracellular cyclic GMP [10], resulting in activation of calcium-dependent kinases, such as calcium-dependent protein kinase (PKC) and Ca2+/calmodulin-de-pendent protein kinase [11]. It should be noted that many aspects of the main WNT signaling routes remain obscure. For example, it is still unclear whether the FZD/PCP and FZD/Ca2+ pathways are distinct or overlapping signaling avenues. Indeed, the involvement of DVL in the FZD/PCP versus FZD/Ca2+ pathway, as well as the involvement of heterotrimeric G proteins, are still matters of debate. Extracellular Frizzled-binding proteins FZDs bind several secreted molecules and some are considered to be cognate ligands (Table 1). The primar