Abstract
Native PKD2-L1 channel subunits are present in primary cilia and other restricted cellular spaces. Here we investigate the mechanism for the channel's unusual regulation by external calcium, and rationalize this behavior to its specialized function. We report that the human PKD2-L1 selectivity filter is partially selective to calcium ions (Ca(2+)) moving into the cell, but blocked by high internal Ca(2+)concentrations, a unique feature of this transient receptor potential (TRP) channel family member. Surprisingly, we find that the C-terminal EF-hands and coiled-coil domains do not contribute to PKD2-L1 Ca(2+)-induced potentiation and inactivation. We propose a model in which prolonged channel activity results in calcium accumulation, triggering outward-moving Ca(2+) ions to block PKD2-L1 in a high-affinity interaction with the innermost acidic residue (D523) of the selectivity filter and subsequent long-term channel inactivation. This response rectifies Ca(2+) flow, enabling Ca(2+) to enter but not leave small compartments such as the cilium.
Highlights
Polycystic kidney disease proteins (PKDs), or polycystins (PC), are divided into two distinct gene families
Calcium binding proteins like calmodulin often bind to Ca2+-permeant ion channels and alter their function (Ben-Johny et al, 2015)
Calcium coordinating motifs within channel proteins, such as cytoplasmic EF-hands found in voltage gated CaV channels, alter channel inactivation based on localized calcium accumulation
Summary
Polycystic kidney disease proteins (PKDs), or polycystins (PC), are divided into two distinct gene families. The three PKD2 members are often included in the TRP ion channel family because they have 6 TM domains and a putative selectivity filter loop between TM5 and TM6 (Ramsey et al, 2006). These include PKD2, (PC2, TRPP1; formerly TRPP2), PKD2-L1 (PC2-L1, TRPP2; formerly TRPP3) and PKD2-L2 (PC2-L2, TRPP3, formerly TRPP5) (Wu et al, 2010). Autosomal dominant polycystic kidney disease (ADPKD) is associated with loss-of-function mutations in genes that encode for either PKD1 or PKD2 (Wu and Somlo, 2000). A putative PKD1-L3 + PKD2-L1 channel was reported in mouse taste buds and proposed to be the acid receptor required for sour taste
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