The Prokineticin receptors (PKR1 and PKR2) are newly identified G-protein coupled receptors that are activated by a unique pair of ligands [6-8,11]. Prokineticins (PK1 and PK2) are cysteine-rich secreted proteins consisting of 81 and 86 amino acids [4,6,11], and are among the largest known GPCR ligands. Recent studies have revealed that the six N-terminal residues of the prokineticins are essential for activating PKR1 and PKR2 [1]. Activation of PKRs leads to mobilization of calcium, phosphoinositide hydrolysis, and activation of PI3 kinase and the mitogen-activated protein kinase (MAPK) pathways [7-8,11]. The involvement of Gi pathways in the receptor signaling transduction, however, is still controversial [4,7-8,11]. While the biology of PKRs is clearly still emerging, published results over the last few years have indicated that PKRs are involved in the regulation of broad functions ranging from angiogenesis, hematopoiesis, neurogenesis, gastrointestinal motility, to circadian rhythms and ingestive behavior [2-6,9-10]. These functions regulated by the PKRs can be classified into two general categories of cell excitability and cell motility, which are consistent with the known signaling transduction mechanisms of PKRs. In a tree of GPCR evolution, PKR1 and PKR2 reside between the neuropeptide receptors and the chemokine receptors, which are known to regulate cell excitability and cell motility, respectively. The unusual high conservation between PKR1 and PKR2 (85% amino acid identity), despite being on different chromosomes, appears to indicate that these receptors are involved in very crucial processes.
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