It is now well appreciated that crucial signaling pathways are located in the cilia. Hedgehog, Wnt, and Notch signaling all occurs in the cilia (Wheway et al., 2018). Importantly, there is specialized G-protein receptor signaling in the cilia. For example, the somatostatin receptor activates adenylyl cyclase 3, which is localized to the cilum. Intriguingly, knocking out the AC3 expressed in neurons of the brain leads to memory deficits in mice (Wang et al., 2011). The past decade of signaling research has led us to the surprising realization that the cilium, while slight in stature, is a crucial hub of signaling.
The restricted localization of receptors and signaling proteins to the cilium suggests that there might be very localized signaling circuits confined to just the small space within the cilium. But what about the freely diffusible second messengers like Ca2+ and cAMP? The Clapham lab targeted a genetically encoded green fluorescent Ca2+ sensor (GCaMP3) to the cilia and found that Ca2+ entry into the Cilia, through TRP channels, was largely confined to the cilia and had little effect on the cytosolic Ca2+ levels. More recently the Mirshahi lab targeted the cADDis sensors to study cAMP levels in the cilia to reveal a fascinating regulation of cAMP levels that was quite different from the adjacent cytosol (Moore et al., 2016).
Order Cilia-Targeted cADDis cAMP Assay Kit
References
K. Hilgendorf, et al. Omega-3 Fatty Acids Activate Ciliary FFAR4 to Control Adipogenesis Cell November, 2019
Follit, J.A., Li, L., Vucica, Y., and Pazour, G.J. (2010). The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. J. Cell Biol. 188, 21–28.
Guemez-Gamboa, A., Coufal, N.G., and Gleeson, J.G. (2014). Primary Cilia in the Developing and Mature Brain. Neuron 82, 511–521.
Moore, B.S., Stepanchick, A.N., Tewson, P.H., Hartle, C.M., Zhang, J., Quinn, A.M., Hughes, T.E., and Mirshahi, T. (2016). Cilia have high cAMP levels that are inhibited by Sonic Hedgehog-regulated calcium dynamics. Proceedings of the National Academy of Sciences 113, 13069–13074.
Sherpa, R.T., Mohieldin, A.M., Pala, R., Wachten, D., Ostrom, R.S., and Nauli, S.M. (2019). Sensory primary cilium is a responsive cAMP microdomain in renal epithelia. Sci. Rep. 9, 6523.
Wang, Z., Phan, T., and Storm, D.R. (2011). The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia. Journal of Neuroscience 31, 5557–5561.
Wheway, G., Nazlamova, L., and Hancock, J.T. (2018). Signaling through the Primary Cilium. Front Cell Dev Biol 6, 8.
