Abstract
DEG/ENaC ion channels are trimeric proteins, forming a heterogeneous group of sodium-selective ion channels sensitive to the inhibitor amiloride. Most family members known so far are impermeable to calcium. Only ASIC 1a (and possibly MEC-4) conduct calcium to a minor extent. To identify ancient properties of this ion channel family, we have recently cloned five new DEG/ENaC subunits from the model organism Hydra magnipapillata. These subunits (HyNaC 1-5) form heterotrimeric channels gated directly by endogenous neuropeptides. Together with FaNaC, a related ion channel from snails, HyNaCs are the only known peptide-gated ion channels. Coinjection of HyNaC 2/3/5 in Xenopus oocytes leads to expression of a peptide-gated cation channel with higher permeability for sodium than for potassium. Here we show that HyNaC 2/3/5 channels have a substantial permeability for calcium, which is in the range of the purinergic P2X4 receptor. In Xenopus oocytes, this calcium influx through HyNaC 2/3/5 strongly activates endogenous calcium-activated chloride channels (CaCCs), leading to a biphasic current. Blocking of the CaCCs reveals a step-like current without apparent desensitization. Moreover, we found that calcium permeability of HyNaCs is largely dependent on a single acidic amino acid at the outer entry of the pore region. Substitution of this acidic residue significantly reduces calcium permeability. The homologous position has been previously reported to be involved in calcium modulation of the related DEG/ENaC channel ASIC 1a (Paukert 2004). Collectively, these results suggest that HyNaCs might play an important role in calcium signalling in vivo.
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