Regenerative Calcium Currents in Renal Primary Cilia

Polycystic kidney disease (PKD) is a leading cause of end-stage renal disease. PKD arises from mutations in proteins, one a Ca(2+)-conducting channel, expressed in the primary cilia of renal epithelial cells. A common hypothesis is that Ca(2+) entering through ciliary ion channels may reduce cystogenesis. The cilia have at least two Ca(2+)-conducting channels: polycystin-2 (PC2) and TRPV4 (transient receptor potential (TRP) cation channel, subfamily V, member 4), but how substantially they can increase intraciliary Ca(2+) is unknown. By recording channel activities in isolated cilia, conditions are identified under which the channels can increase free Ca(2+) within the cilium by at least 500-fold through regenerative (positive-feedback) signaling. Ca(2+) that has entered through a channel can activate the channel internally, which increases the Ca(2+) influx, and so on. Regenerative signaling is favored when the concentration of the Ca(2+) buffer is reduced or when a slower buffer is used. Under such conditions, the Ca(2+) that enters the cilium through a single PC2 channel is sufficient to almost fully activate that same channel. Regenerative signaling is not detectable with reduced external Ca(2+). Reduced buffering also allows regenerative signaling through TRPV4 channels, but not through TRPM4 (TRP subfamily M, member 4) channels, which are activated by Ca(2+) but do not conduct it. On a larger scale, Ca(2+) that enters through TRPV4 channels can cause secondary activation of PC2 channels. I discuss the likelihood of regenerative ciliary Ca(2+) signaling in vivo, a possible mechanism for its activation, and how it might relate to cystogenesis.