Biological activities of Bv8 analogues.
1 The small protein Bv8, secreted by the skin of the frog Bombina variegata, belongs to a novel family of secreted proteins whose orthologues have been identified in snakes (MIT) and in mammals (prokineticins (PKs)). A characteristic feature of this protein family is the same N-terminal sequence, AVITGA, and the presence of 10 cysteines with identical spacing in the C-terminal domain. Two closely related G protein-coupled receptors that mediate signal transduction of Bv8/PKs have been cloned (PK-R1 and PK-R2). In mammals, the Bv8/PK protein family is involved in a number of biological activities such as ingestive behaviours, circadian rhythms, angiogenesis and pain sensitization. 2 In an attempt to identify the structural determinants required for the pronociceptive activity of Bv8, we prepared Bv8 derivatives lacking one (des-Ala-Bv8) or two (des-Ala-Val-Bv8) residues from the N-terminus. 3 des-Ala-Bv8 displayed a receptor affinity five times lower than that of Bv8, it was five times less potent in inducing [Ca(2+)](i) transients and in causing p42/p44 MAPK phosphorylation in CHO-cells expressing PK-R1 and PK-R2. Moreover, dA-Bv8 was about 20 times less potent than Bv8 in inducing hyperalgesia in rats. 4 The deletion of the first two amino acids of Bv8 abolished any biological activity both 'in vitro' and 'in vivo'; however, des-AlaVal-Bv8 is able to antagonize the Bv8-induced hyperalgesia, binding the PK-Rs on peripheral and central projections of the primary sensitive neurons.
Negri
Lucia
L
Dipartimento di Fisiologia Umana e Farmacologia V. Erspamer, Università La Sapienza, Roma, Italy. lucia.negri@uniroma1.it
Lattanzi
Roberta
R
Giannini
Elisa
E
Colucci
Maria Antonella
MA
Mignogna
Giuseppina
G
Barra
Donatella
D
Grohovaz
Fabio
F
Codazzi
Franca
F
Kaiser
Alessandra
A
Kreil
Guenther
G
Melchiorri
Pietro
P
D029845:Amphibian Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced; D010766:Phosphorylation; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013329:Structure-Activity Relationship
D029845:Amphibian Proteins; C121344:Bv8 protein, Bombina variegata; D009479:Neuropeptides; C470837:PROKR1 protein, human; D043562:Receptors, G-Protein-Coupled; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium