K+ pump: From caterpillar midgut to human cochlea

Deafness is a serious condition that affects millions of people and can also lead to dementia. Moreover, Karet and associates reported in 1999 that mutations in the gene encoding H+ V-ATPase subunit B1 lead to deafness. Yet ionic flows that enable humans to hear high-pitched sounds at 20,000 cycles/sec (20 kHz) are not well understood. Sound is transduced to electrical signals by stereocilia of hair cells by influx of Ca2+ and K+ as the “transducer channel” opens transiently and reduces the ∼90 mV (endolymph positive) endocochlear potential (EP) by ∼20 mV as the receptor potential. The EP as well as concentrations of Ca2+, H+ and K+ must remain constant to produce reliable signals. Ca2+ entry is balanced by Ca2+ exit via a plasma membrane Ca2+ ATPase (PMCA2a) but the Ca2+ exit is coupled to H+ entry. Moreover, K+ entry is balanced by K+ exit via a long diffusion route through several channels which is too slow to account for 20 kHz signaling. The problem is solved by a new hypothesis in which an H+ V-ATPase generates the EP and removes the H+ while a new K+/H+ antiporter uses the voltage to drive H+ back in and the K+ back out. In the new model, Ca2+, H+ and K+ cycle between unstirred layers on the endolymph- and cytoplasmic- borders of the stereocilial membrane through distances of ∼20 nanometers with travel time of ∼10 μs, which is fast enough to account for the 50 μs open/close time for 20 kHz signaling. Central to this model is the hypothesis that a K+ pump which secretes K+ into a K+-rich compartment is composed of a voltage producing (electrogenic) H+ V-ATPase that is electrically coupled to a voltage-driven (electrophoretic) K+/nH+ antiporter (KHA). Conversely, for an H+ V-ATPase to secrete K+ into a K+ rich compartment, it must be coupled to a KHA. Richard Keynes reviewed evidence in 1969 that such a K+ pump, which he called a Type V pump, is present in the stria vascularis of cochlea and the goblet cell apical membrane of caterpillars. Its signature is a large outside positive potential of ∼100 mV, K+ secretion into a K+ rich compartment and reversible inhibition by anoxia. The key role of the Type V K+ pump in generating the EP was recognized by Sellick and Bock in 1974 and others but has disappeared from the hearing literature during the past decades. Its revival here is based on immunolocalization of KHA2 in the stereocilial membrane and Gillespie’s generously shared mass spectroscopy evidence that all but one of the V1 ATPase subunits are detected in isolated chicken stereocilia but Vo and KHAs are not detected (implying that KHAs must be in the membrane). The new model proposed in the present paper could lead to important changes in our understanding of sensory physiology.

Figure optionsDownload as PowerPoint slideHighlights
► The endocochlear potential in stereocilia is deduced to be a K+ pump potential.
► The K+ pump is known to be an H+ V-ATPase: K+/H+ antiporter (KHA) pair.
► H+ V-ATPase and KHA are postulated to be in the plasma membrane of cochlear stereocilia.
► The K+ pump in hair-, supporting- and stria-cells is postulated to be an H+ V-ATPase: KHA pair.
► Ca2+, H+ and K+ are postulated to cycle rapidly in unstirred layers of cochlear stereocilia.