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Stresscopin & Urocortin Information  

Novel specific ligands for CRF receptor type 2

The recently deposited genome sequences afford a novel procedure for discovering putative ligands utilizing the sequence homology with existing ligands. This promising method has now been applied to the discovery of the selective ligands for the corticotropin releasing factor (CRF) receptor type 2 (CRF-R2).

CRF receptors, CRF-R1 and CRF-R2, belong to the superfamily of G-protein coupled receptors with seven transmembrane domains. A well-established ligand for CRF-R1 is CRF [Code 4136 (human) and Code 4111 (ovine)], whereas urocortin [Code 4328 (human) and Code 4327 (rat)] is the non-selective but potent ligands for CRF-R1 and CRF-R2[Endocrinology, 137, 2167 (1996)]. Selective ligand(s) with distinct CRF-R2 preference have not been identified until very recently, when two groups proposed urocortin II/III [Proc. Natl. Acad. Sci. USA, 98, 2843 (2001), ibid. 98, 7570 (2001)] or stresscopin/stresscopin-related peptide, discovered by independently applying the above mentioned method[Nat. Med., 7, 605 (2001)].

Urocortin II, a 38 amino acid residue peptide with an amidated C-terminus, was first predicted in mouse from a gene encoding a 112 amino acid residue [Proc. Natl. Acad. Sci. USA, 98, 2843 (2001)]. Simultaneously, human urocortin II (originally named as urocortin-related peptide) was postulated to be composed of the same 38 amino acid residues, although its carboxyl terminal extra-sequence is far from the common proteolytic processing signal, that is, Gly-His-Cys. Subsequently, a similar peptide, stresscopin-related peptide, was putatively identified in human, representing a 5 amino acid-extended urocortin II at the amino terminus. Stresscopin, a homologous peptide with stresscopin-related peptide (or urocortin II), was thus postulated to be a 40 amino acid residue peptide, which follows the amide-donating Gly residue and then the Arg-Lys-Lys processing signal in the gene sequence. An amino terminal truncated peptide (des-Thr-Lys), or urocortin III [Proc. Natl. Acad. Sci. USA, 98, 7570 (2001)], was proposed soon after the publication of stresscopin. All five of these peptides, please see summary below, have just been proposed from the gene sequence; therefore, the exact processing sites of these peptides should be determined by isolating the corresponding endogenous peptides.

Both chemically synthesized urocortin II/III and stresscopin / stresscopin-related peptide bind to and activate CRF-R2 (two isoforms, α and β) selectively at nM concentrations or below. Actually, all the peptides stimulate the accumulation of cAMP through CRF-R2 but not CRF-R1. In addition, the ACTH releasing activity is not elicited by treatment with these peptides, indicating again the specific activation of CRF-R2. Additional activities involving the mediation of anorexicand vascular responses following stress are also attributed to these peptides: 1) suppression of heat-induced edema which is associated with hypotensive effect of these peptides, 2) feeding suppression in fasted mice, 3) a suppressive role in gastric emptying activity, and so on. Transcriptional and immunohistochemical analyses revealed that these peptides are expressed both centrally and peripherally with some differences in tissue distribution.

UCN II (Mouse):



VILSLDVPIG
LLRILLEQAR
YKAARNQAAT
NAQILAHV-NH2


UCN II (Human):



IVLSLDVPIG
LLQILLEQAR
ARAAREQATT
NARILARV-NH2


SRP (Human):


HPGSR
IVLSLDVPIG
LLQILLEQAR
ARAAREQATT
NARILARV-NH2


SCP (Human):


TK
FTLSLDVPTN
IMNLLFNIAK
AKNLRAQAAA
NAHLMAQI-NH2


UCN III (Human):



FTLSLDVPTN
IMNLLFNIAK
AKNLRAQAAA
NAHLMAQI-NH2

Huge experimental data concerning CRF-R1-mediated responses have already been accumulated using CRF. Therefore, adaptive responses to stress could be investigated more precisely and promptly using CRF-R2 specific ligands, stresscopin/urocortin family peptides.

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