Dataset Information

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.

SUBMITTER: Lattanzi R

PROVIDER: S-EPMC8877203 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Prokineticin-Receptor Network: Mechanisms of Regulation.

Lattanzi Roberta R Miele Rossella R

Life (Basel, Switzerland) 20220125 2

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; prokineti ...[more]

PMID: 35207461

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Project description:BackgroundThe suprachiasmatic nucleus (SCN) contains the master circadian clock that regulates daily rhythms of many physiological and behavioural processes in mammals. Previously we have shown that prokineticin 2 (PK2) is a clock-controlled gene that may function as a critical SCN output molecule responsible for circadian locomotor rhythms. As light is the principal zeitgeber that entrains the circadian oscillator, and PK2 expression is responsive to nocturnal light pulses, we further investigated the effects of light on the molecular rhythm of PK2 in the SCN. In particular, we examined how PK2 responds to shifts of light/dark cycles and changes in photoperiod. We also investigated which photoreceptors are responsible for the light-induced PK2 expression in the SCN. To determine whether light requires an intact functional circadian pacemaker to regulate PK2, we examined PK2 expression in cryptochrome1,2-deficient (Cry1-/-Cry2-/-) mice that lack functional circadian clock under normal light/dark cycles and constant darkness.ResultsUpon abrupt shifts of the light/dark cycle, PK2 expression exhibits transients in response to phase advances but rapidly entrains to phase delays. Photoperiod studies indicate that PK2 responds differentially to changes in light period. Although the phase of PK2 expression expands as the light period increases, decreasing light period does not further condense the phase of PK2 expression. Genetic knockout studies revealed that functional melanopsin and rod-cone photoreceptive systems are required for the light-inducibility of PK2. In Cry1-/-Cry2-/- mice that lack a functional circadian clock, a low amplitude PK2 rhythm is detected under light/dark conditions, but not in constant darkness. This suggests that light can directly regulate PK2 expression in the SCN.ConclusionThese data demonstrate that the molecular rhythm of PK2 in the SCN is regulated by both the circadian clock and light. PK2 is predominantly controlled by the endogenous circadian clock, while light plays a modulatory role. The Cry1-/-Cry2-/- mice studies reveal a light-driven PK2 rhythm, indicating that light can induce PK2 expression independent of the circadian oscillator. The light inducibility of PK2 suggests that in addition to its role in clock-driven rhythms of locomotor behaviour, PK2 may also participate in the photic entrainment of circadian locomotor rhythms.

Dataset Information

Prokineticin-Receptor Network: Mechanisms of Regulation.

Publications

Prokineticin-Receptor Network: Mechanisms of Regulation.

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