Compartmentalised cAMP signalling in the primary cilium

Abstract

cAMP is a universal second messenger that relies on precise spatio-temporal regulation to control varied, and often opposing, cellular functions. This is achieved via selective activation of effectors embedded in multiprotein complexes, or signalosomes, that reside at distinct subcellular locations. cAMP is also one of many pathways known to operate within the primary cilium. Dysfunction of ciliary signaling leads to a class of diseases known as ciliopathies. In Autosomal Dominant Polycystic Kidney Disease (ADPKD), a ciliopathy characterized by the formation of fluid-filled kidney cysts, upregulation of cAMP signaling is known to drive cystogenesis. For decades it has been debated whether the primary cilium is an independent cAMP sub-compartment, or whether it shares a diffusible pool of cAMP with the cell body. Recent studies now suggest it is a specific pool of cAMP generated in the cilium that propels cyst formation in ADPKD, supporting the notion that this antenna-like organelle is a compartment within which cAMP signaling occurs independently from cAMP signaling in the bulk cytosol. Here we present examples of cAMP function in the cilium which suggest this mysterious organelle is home to more than one cAMP signalosome. We review evidence that ciliary membrane localization of G-Protein Coupled Receptors (GPCRs) determines their downstream function and discuss how optogenetic tools have contributed to establish that cAMP generated in the primary cilium can drive cystogenesis.

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

“…The primary cilium is a highly complex structure that contains many receptors, second messengers and ion channels 76,87,88 , some of which have been implicated in nociceptor function. One such primary cilium-dependent signaling pathway is Hh.…”

“…In the present experiments treatment with an siRNA for Ift88 markedly attenuated the mechanical hyperalgesia induced by PGE2. Again, how the primary cilium, located as a protrusion from the nociceptor cell body, which contains elements of signaling pathways implicated in nociceptor sensitization (e.g., adenylyl cyclase [76][77][78] ), contributes to sensitization of nociceptors, at their peripheral and central terminals, remains to be explored.…”

Purine nucleosides replace cAMP in allosteric regulation of PKA in trypanosomatid pathogens

“…Reconciling a second messenger function with the role of metabolites in the cell seems less of a conceptual problem. First, an increasing number of metabolites with signalling function emerge (Baker and Rutter 2023) and second, subcellular compartmentalization of signal generation/degradation is well established for cAMP signalling and PKA that act mostly in microdomains (Buxton and Brunton 1983; Zaccolo, Zerio, and Lobo 2021; Paolocci and Zaccolo 2023; Musheshe, Schmidt, and Zaccolo 2018). In fact, PKA of the trypanosomatid species analysed here is predominantly localized in the flagellum (Bachmaier et al 2016; Oberholzer et al 2011; Billington et al 2023), a confined compartment that serves as sensory organelle of the cell (Bachmaier et al 2022; Ooi and Bastin 2013; Oberholzer et al 2010).…”

Contribution of membrane-associated oscillators to biological timing at different timescales

“…The mechanisms of homeostatic plasticity are intimately connected to PTFL oscillators that constitute localized signaling cascades, termed signalosomes. Signalosomes are multimolecular complexes that anchor complete signal transduction cascades from the receptor to effectors at distinct cellular locations, such as to the plasma membrane, through scaffolding molecules ( Dunn and Ferguson, 2015 ; Zaccolo et al, 2021 ; Excoffon et al, 2022 ; Ma et al, 2023 ; Paolocci and Zaccolo, 2023 ). They allow for compartmentalization of intracellular (second) messengers in subcellular nanodomains ( Zaccolo et al, 2021 ).…”