The prokineticins: a novel pair of regulatory peptides

Abstract

Secreted peptides play broad regulatory roles in brain function and elsewhere in the body. Prokineticins are a pair of newly identified regulatory peptides that signal through two highly homologous G protein-coupled receptors. Prokineticins possess a unique structural motif of five disulfide bonds and a completely conserved N-terminal hexapeptide sequence that is essential to biological activity. Diverse biological functions, including roles in development and cell differentiation, have been assigned to the prokineticins. A network of genes, subject to various transcriptional factors, may functionally converge on the prokineticins as regulatory targets.

Figure 1. Biological functions of prokineticins

Prokineticins (PK1 and PK2) are a pair of cysteine-rich secreted molecules that exert their functions via activation of two G protein–coupled receptors (PKR1 and PKR2). Prokineticins are versatile molecules that regulate multiple biological processes, with apparent selectivity of ligand/receptor pairing. In particular, PK2/PKR2 signaling is critical for circadian clock output and neurogenesis of the olfactory bulb (OB), whereas the PK2/PKR1 pair plays a dominant role in pain perception. Prokineticins also regulate other processes, including gastrointestinal smooth muscle motility, angiogenesis, and hematopoiesis, where the involvement of ligand/receptor pairing is largely unexplored. The dashed arrow implies that PK1 and PKR2 may form a complex in unidentified functions.

Figure 2. Amino acid sequences of human PKs and their analogs from frog and snake

The sequences of human PK1 (red) and PK2 (orange) are compared to that of frog (green) and snake (blue). The conserved N-terminal hexapeptide is highlighted in yellow. Ten conservative cysteine residues are highlighted in purple. Adapted from (6).

Figure 3. Transcriptional regulation of prokineticin 2

The promoter of the PK2-encoding gene, in both human and mouse, contains multiple E-box sequences (CACGTG) that are targeted by basic helix-loop-helix (bHLH) transcription factors (ovals; CLOCK/BMAL1 and Ngn1/MASH1 dimers are schematized here). The expression of PK2 (orange) is a common functional target for both sets of transcriptional factors, although distinct biological processes are ultimately affected, depending the particular transcriptional machinery that is recruited (indicated by different shades of blue arrows). PK2 is also induced by hypoxia (as is PK1), and thus HIF-1 (hypoxia-inducing factor, also a bHLH transcription factor) may also regulate the functionality of PK2. (The dashed outline around Ngn1 is intended to indicate the speculative nature of its specific transcriptional role in this instance. See text for details.)