A cDNA encoding guinea-pig uterine substance P (SP) receptor has been isolated using the homology screening approach. Northern blot analysis reveals that the corresponding mRNA, of approx. 4.8 kb, is expressed in all tissues tested, but predominantly in the uteri of non-pregnant animals; during pregnancy its expression is reduced. The guinea-pig SP receptor was expressed in COS-7 cells and demonstrated relative Iigand affinity in the order: SP » neurokinin A > neurokinin B.Substance P (SP) belongs to the tachykinin family of peptides which includes, in addition to SP, the peptides substance K (neurokinin A) and neuromedin K (neurokinin B). The tachykinins share a common carboxylterminal sequence and give rise to similar spectra of biological activity. SP was the first of these neuropeptides tobe discovered, and is the best characterized. It causes smooth muscle contraction and vasodilation, and plays a role in neuron excitation, pain ttansmission and netve regeneration [1,2]. An important target organ for SP is the uterus. lrnmunocytochemical studies have shown that numerous SP-positive neurons innervate the myometrium and uterine arteries [3][4][5]. SP, in combination with other neuropeptides, plays an essential role in the regulation of myometrial activity and, consequently, in the maintenance of pregnancy and parturition.SP exerts its effect via the SP receptor (so called . NK-1 receptor ), a G-protein-coupled receptor which utilises the phosphatidyl inositol second messenger system.cDNAs corresponding to the rat [6,7] and human [8] SP receptors have recently been cloned and characterized. Here we report the molecular cloning of the guinea-pig SP receptor cDNA and its expression in COS cells. The aim of our study was the isolation of cDNAs corresponding to neuropepÜde receptors expressed in the guinea-pig uterus. These are G-protein-coupled receptors that share common structural features and have consetved amino acid sequences, particularly within the transmembrane domains. Therefore, we chose the homology screening approach to analyse guinea-pig uterine cDNA library constructed in ,\gtlO bacteriophage. A degenerate oligonucleotide (5'-GG2A~CCAGCAGA