Prokineticin-Receptor Network: Mechanisms of Regulation

Abstract

Prokineticins are a new class of chemokine-like peptides that bind their G protein-coupled receptors, PKR1 and PKR2, and promote chemotaxis and the production of pro-inflammatory cytokines following tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms of prokineticins pathway regulation that, like other chemokines, include: genetic polymorphisms; mRNA splice modulation; expression regulation at transcriptional and post-transcriptional levels; prokineticins interactions with cell-surface glycosaminoglycans; PKRs degradation, localization, post-translational modifications and oligomerization; alternative signaling responses; binding to pharmacological inhibitors. Understanding these mechanisms, which together exert substantial biochemical control and greatly enhance the complexity of the prokineticin-receptor network, leads to novel opportunities for therapeutic intervention. In this way, besides targeting prokineticins or their receptors directly, it could be possible to indirectly influence their activity by modulating their expression and localization or blocking the downstream signaling pathways.

Substance P and Prokineticin-2 are overexpressed in olfactory neurons and play differential roles in persons with persistent post-COVID-19 olfactory dysfunction

“…Otherwise, the higher PK2 expression could be simply related to the regeneration of the olfactory structures, consistently with the physiological role of the chemokine ( Lattanzi and Miele, 2022 , Ng et al, 2005 ).…”

“…PK2 primary transcript undergoes two alternative splice variants, PK2 and PK2-long (PK2L). PK2L is expressed only in peripheral tissues, while PK2 also in the brain ( Lattanzi and Miele, 2022 , Negri and Ferrara, 2018 ), in the olfactory system in particular. PK2 participates in several physiological and neurodevelopmental processes via two different G-protein coupled receptors (PKR1 and PKR2), ubiquitously present in the entire CNS ( Negri and Ferrara, 2018 ).…”

“…Moreover, the PK2 levels were directly correlated with their residual olfaction (quantified through Sniff’s test IS), suggesting that a greater PK2 expression in ONs might contribute recovering OD better. Indeed, the PK2 pathway could be activated in ONs by pathological triggers, including inflammation, and participate in a wide neuroprotective response, as it occurs in other neurological conditions ( Bao et al, 2021 , Gordon et al, 2016 , Lattanzi et al, 2021 , Lattanzi and Miele, 2022 , Maftei et al, 2022 , Negri and Ferrara, 2018 ). There is experimental evidence that PK2 prevents neuronal death, enhances mitochondrial bioenergetics, promotes protective Nrf-2 mediated effects, and finally induces a down-toning of inflammation, favouring a phenotypic shift in immune cells even at the CNS level ( Neal et al, 2018 ).…”

Arginine 125 Is an Essential Residue for the Function of MRAP2

“…In contrast, PK2β, an alternative splicing short isoform of PK2 composed of only 47 amino acids, shows limited ability to induce STAT3 phosphorylation and leads to increased food intake [ 6 , 7 , 8 ]. In adipocytes, PK2 limits preadipocyte proliferation and differentiation by binding to PKR1 to control adipose tissue expansion [ 9 , 10 ].…”

Non-Peptide Agonists and Antagonists of the Prokineticin Receptors

“…All proteins share a common structure characterized by a conserved N-terminal sequence consisting of alanine, valine, isoleucine, triptophan, glicin, and alanine. For this reason, they are also called AVITGA proteins [ 6 , 7 ]. PKs are also characterized by 10 cysteine residues forming five disulfide bridges and a tryptophan residue at position 24, which is crucial for receptor binding.…”