A cDNA clone encoding a novel G protein h subunit of h1 subclass, pfGh1 was isolated from the pearl oyster (Pinctada fucata). The deduced amino acid sequence of pfGh1 (341 amino acids) shares high homology to northern European squid (Loligo pealei) and great pond snail (Lymnaea stagnalis) Gh1, while it has diverged from bovine (Bos taurus) and human. The well-conserved amino acid domains in G protein h subunit, seven WD repeats, were founded in the deduced amino acid sequence. Alignment analysis showed that the beginning amino acid residues in variable fragment of the seventh WD motif are different from any other Gh. The prediction of 3D structure of pfGh showed that pfGh belongs to h-propeller family proteins whose members contain 4–8 antiparallel h-sheets resembling the blades of a propeller. In situ hybridization and Northern blotting analysis revealed that the pfGh mRNA hybridization signals were widely expressed in various tissues except muscle, with abundantly in epithelia of gill, gonad and outer fold of mantle. We also investigated the interactions between Ghg and calmodulin (CaM), and specific amino acid residues that may be critical for the binding of Ghg to CaM were also identified. Furthermore, the functional studies of the interaction showed that the binding of CaM and Ghg increases the alkaline phosphatase (ALP) activity, an indicator for mineralization in MC3T3-E1 cells. The ALP activity of the mutants of pfGhg that impaired the interactions of Ghg with CaM is higher than the Control group; however, it is lower than the WTC group. Together, these results suggest that the Ghg might interact with CaM and point to the important physiological function in modulating cellular functions.