Neurokinin A (substance K) is a peptide neurotransmitter of the tachykinin family with potential as a major mediator in human airway and gastrointestinal tissues.'.'Neurokinin A acts via a receptor (the NK-2 receptor) that is believed to be localized on smooth muscle cells and pharmacologically coupled to a GTP-binding protein.'To characterize the human NK-2 receptor, we prepared a partial cDNA from human tracheal RNA using the polymerase chain reaction with oligonucleotide primers derived from the bovine NK-2 receptor cDNA sequence: This partial human NK-2 receptor cDNA was used to screen a human genomic DNA library and yielded a clone, NGNK-2, of approximately 20 kilobase pairs. Analysis of NGNK-2 indicates that it contains the entire coding sequence of the NK-2 receptor as well as 5'and 3'flanking sequences. The gene is organized with five exons interrupted by four introns. We determined the complete sequence of the exons and the intron/exon junctions, as well as the transcription initiation site at nucleotide-222 and the 3'polyadenylation signal at nucleotide 1530. Sequence analysis of exons 1 and 5, where major differences occur between the human and animal species, provided information for PCR primers that allowed us to prepare full-length cDNA for the human NK-2 receptor. The protein predicted from the gene sequence is extended by 14 amino acids at the C-terminus compared to the bovine molecule and by 9 residues compared to the rat molecule (FIGURE 1). The seven membrane-spanning regions are encoded by exons 1-4 and none are interrupted by introns. These regions are highly conserved among the species studied, suggesting stringent evolutionary control over these molecules. aThis work was supported in part by NIH Grant No. HL41. 587. rN. P. Gerard is the recipient of NIH Research Career Development Award No. HU1777. eC. Gerard is the recipient of a Faculty Scholars Award from RJR Nabisco.