Calmodulin (CaM), the Ca²⁺ sensor in living cells, is essential for biological functions mediated by Ca²⁺-dependent mechanisms. However, modulation of CaM gene expression at the pituitary level as a means to regulate pituitary hormone synthesis has not been characterized. Here we examined the functional role of CaM in the feedback control of growth hormone (GH) by insulin-like growth factor (IGF) using grass carp pituitary cells as a cell model. To establish the structural identity of CaM expressed in the grass carp, a CaM cDNA, CaM-L, was isolated from the carp pituitary using 3'/5' RACE. The ORF of this cDNA encodes a 149 a.a. protein sharing the same primary structure with CaMs reported in mammals, birds, and amphibians. This CaM cDNA is phylogenetically related to the CaM I gene family and its transcripts are ubiquitously expressed in the grass carp. In carp pituitary cells, IGF-I and -II induced CaM mRNA expression with a concurrent drop in GH transcript levels. These stimulatory effects on CaM mRNA levels were not mimicked by insulin and appeared to be a direct consequence of IGF activation of CaM gene transcription without altering CaM transcript stability. CaM antagonism and inactivation of calcineurin blocked the inhibitory effects of IGF-I and -II on GH gene expression and CaM over-expression also suppressed the 5' promoter activity of grass carp GH gene. These results, as a whole, provide evidence for the first time that IGF feedback on GH gene expression is mediated by activation of CaM gene expression at the pituitary level.