AVIT (prokineticin) family

General Prokineticins (PKs) are a family of secreted proteins that have diverse regulatory roles in all vertebrates and display many characteristics reminiscent of cytokines. They were originally identified as potent agents stimulating smooth-muscle contraction in the guinea-pig gastrointestinal tract. They have also been shown to modulate complex behaviors, such as feeding, drinking, and circadian rhythms, as well as hormone secretion, neurogenesis, neuronal survival, angiogenesis, pain sensation (nociception), and the development of certain tissues. PKs have also been implicated in pathologies of the reproductive system, myocardial infarction, and tumorigenesis. PK family members are cysteine-rich proteins of about 8 kDa that share a similar framework of ten cysteine residues that form five disulfide bridges, and a highly conserved N-terminal AVITG motif that is crucial for activity. In humans, three PK isoforms have been identified: PK1, also termed endocrine gland-derived vascular endothelial growth factor (EG-VEGF), PK2 (also termed protein Bv8 homolog), and PK2β. The diverse biological effects of PKs are mediated through two G protein-coupled receptors (GPCRs), PK receptors PROKR1 and PROKR2, which bind PKs with subnanomolar affinity. PROKR1 and PROKR2 belong to the neuropeptide Y receptor class and couple to Gq, Gi, and Gs G proteins to promote intracellular calcium mobilization, activation of MAP kinase, and cAMP accumulation, respectively (Morales et al., 2010 and references therein).

Interestingly, PKs have also been identified in snake venoms (mamba intestinal toxin 1, MIT-1) and in the skin secretions of frogs (Bombina variegata protein of 8 kDa, Bv8), as well as in some invertebrates. MIT-1 and Bv8 are the most potent PKs described to date, with at least tenfold higher affinity (picomolar range) for PROKR1 and PROKR2 than the orthologous mammalian proteins. This feature makes them ideal biochemical tools to study PK function in more detail. However, despite a rapidly growing body of evidence implicating PKs in key physiological processes, their precise roles are still poorly defined. This is partially due to colocalization of PROKR1 and PROKR2, and their lack of PK selectivity. Hence, redundancy and compensation effects make it difficult to dissect the pathways and biological outcomes associated with PROKR1 or PROKR2 (Morales et al., 2010 and references therein).