Calcitonin receptor (CTR) is a member of class B G protein-coupled receptor (GPCR) superfamily. We have recently identified the CTR gene and its two transcriptional isoforms, mfCTR and mfCTR Delta N, in mefugu (mf) (Takifugu ohscurus). Here we characterized the mfCTR Delta N that lacks hormone-binding extracellular N-terminal domain. Strong expression in the liver and weak but broad tissue distribution of its mRNA, revealed by Northern analysis, suggested physiological significance of this headless splice variant. Biochemical and immunocytochemical analyses revealed that it acts as a naturally occurring dominant negative isoform by forming a heterodimer with normal CTR. The headless mfCTR Delta N characterized here is the first case of N-terminally truncated dominant negative form of GPCR, and immunocytochemistry used for detecting the heterodimer formation may be useful as a novel method for analyzing membrane protein interaction in a living cell. (C) 2007 Elsevier Inc. All rights reserved.