Trends in Cell Biology

Trends in Cell Biology

Volume 20, Issue 8, August 2010, Pages 435-444
Journal home page for Trends in Cell Biology

Opinion
cAMP and cGMP signaling: sensory systems with prokaryotic roots adopted by eukaryotic cilia

https://doi.org/10.1016/j.tcb.2010.05.005Get rights and content

An exciting discovery of the new millennium is that primary cilia, organelles found on most eukaryotic cells, play crucial roles in vertebrate development by modulating Hedgehog, Wnt and PDGF signaling. Analysis of the literature and sequence databases reveals that the ancient signal transduction pathway, which uses cGMP in eukaryotes or related cyclic di-GMP in bacteria, exists in virtually all eukaryotes. However, many eukaryotes that secondarily lost cilia during evolution, including flowering plants, slime molds and most fungi, lack otherwise evolutionarily conserved cGMP signaling components. Based on this intriguing phylogenetic distribution, the presence of cGMP signaling proteins within cilia, and the indispensable roles that cGMP plays in transducing environmental signals in divergent ciliated cells (e.g. vertebrate photoreceptors and Caenorhabditis elegans sensory neurons), we propose that cGMP signaling has a strong ciliary basis. cAMP signaling, also inherent to bacteria and crucial for cilium-dependent olfaction, similarly appears to have widespread usage in diverse cilia. Thus, we argue here that both cyclic nucleotides play essential and potentially ubiquitous roles in modulating ciliary functions.

Section snippets

Introduction: cilia – origin, structure and function

The primordial eukaryote is inferred to have possessed on its surface one or two antenna-shaped organelles, termed cilia, used for environmental sensing and locomotion 1, 2. Cilia were propagated throughout evolution to most extant unicellular and multicellular eukaryotic organisms, with some notable exceptions where secondary losses occurred, such as in higher plants, almost all fungi and amoeba 1, 2. Testifying to their monophyletic origin, all ciliary axonemes are templated from a

Archetypal cGMP signaling pathway in the photoreceptor ciliary compartment

A representative cGMP signaling pathway, set within a generic ciliary compartment (e.g. photoreceptor), is presented in Figure 1. Relevant cGMP signaling components, together with summaries of their functions, are listed in Table 1. Multiple pathways for cGMP signaling are known [25]. In one pathway, activation of a G-protein coupled receptor (GPCR) can trigger G-protein signaling and result in either the synthesis or hydrolysis of cGMP via a GC or PDE, respectively [23]. A second pathway

cAMP signaling in vertebrate olfactory cilia

Use of cGMP as a signal amplification cascade in photoreception is extremely efficient – single photons result in neuronal activation from the hydrolysis of 15 000–500 000 cGMP molecules [23]. An analogous amplification system is well characterized in vertebrate/mammalian ciliated olfactory neurons, which are responsible for smell 42, 43. In these neurons, odorants bind specific GPCRs that stimulate adenylate cyclase (AC) to produce cAMP. This second messenger in turn opens cAMP-gated channels

cAMP signaling in most non-motile and motile cilia?

Evidently, vertebrate/mammalian cilia orchestrate both cGMP and cAMP signal transduction in addition to the oft-mentioned Hedgehog, Wnt and PDGF signaling pathways. In fact, a key player in cAMP signaling, Adenylate Cyclase III (ACIII), is typically used as a general ciliary marker, owing to its presence not simply in olfactory cilia but within primary cilia of mammalian kidney, most brain neurons, and other cell types 47, 48. cAMP signaling components are also important for regulating ciliary

C. elegans cGMP signaling components localize to cilia and are important for most sensory modalities and behaviors

At the whole-organism level, cGMP signaling is arguably best understood in C. elegans 52, 53. The nematode boasts virtually all known cGMP signaling components, largely paralleling those found in ciliary photoreceptors (Table 1). The expression patterns of nearly all C. elegans guanylate cyclases (34 in total) and cGMP-gated channels (e.g. TAX-2 and TAX-4; orthologs of CNGB1 and CNGA1, respectively) have been determined, and with few exceptions, are restricted to ciliated sensory neurons (

Cilium-dependent cyclic nucleotide signaling: examples from other organisms

In addition to the cilium-associated functions of cyclic nucleotides described above for vertebrates and C. elegans, cGMP and cAMP are also central for ciliary signaling in other organisms. For example, in the green alga Chlamydomonas reinhardtii, initiation of mating events, a sensory-related process involving ciliary tip extension and adhesion, is dependent on increased cilium-associated cAMP and guanylate cyclase activity [66]. One effector of cGMP signaling, the PKG protein CrPKG, was found

cGMP signaling components: almost exclusively confined to ciliated organisms

The seemingly strict correspondence between cilia and cGMP signaling in C. elegans prompted us to examine the phyletic distribution of cGMP signal transduction proteins in ciliated and non-ciliated organisms from a broad sampling of Phyla. This revealed a remarkable pattern – organisms possessing cilia (metazoans and ciliated protists) almost invariably encode cGMP-associated GCs, PDE and regulatory subunits PDE6δ and PDE6γ, PKG, and CNG channels, whereas species lacking cilia mostly lack these

The most ancient signaling pathways adopted by the proto-cilium?

A pivotal development during eukaryogenesis was the inception of a ciliary organelle [2]. It can be argued that the earliest evolutionary step required for establishing a proto-cilium was the formation of a sensory patch on the cell membrane, generated via the microtubule-dependent trafficking of vesicle-associated sensory molecules (e.g. receptors). This clustering of signaling components could have enhanced signaling efficiency and conferred a selective advantage; subsequently, more complete

Conclusions

Primary cilia unquestionably have the form and function of cellular antennae optimized to orchestrate intracellular signaling events. In this review, we have underscored the close relationship between cilia and cyclic nucleotide signal transduction pathways, both of which are evolutionarily more ancient than other signaling pathways (Hedgehog, Wnt and PDGF) customarily associated with cilia 4, 10, 11, 12, 16. Although profound questions regarding the cilium-cGMP/cAMP signaling connection remain

Acknowledgments

Our sincere apologies to the numerous researchers whose important studies could not be cited owing to space constraints. We thank Dr. Lynne Quarmby for reviewing this manuscript, and the Canadian Institutes of Health Research (CIHR; grant MOP-97956) for funding this work. M.R.L. is the recipient of a Michael Smith Foundation for Health Research (MSFHR) senior scholar award.

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