Of ATPase activity, cellular energy distribution, and linking depolarization and division

Abstract

This month's installment of Generally Physiological considers how differences in Na-pump K + affinity and localiza-tion enable their efficient operation over the range of [K + ] o in resting and active muscle, how a mitochondrial re-ticulum could enable the rapid distribution of energy throughout skeletal muscle, and how signaling from K-Ras may link membrane depolarization with cell proliferation. The fractional occupancy of sub-strate sites by Na + and K + provides a primary mechanism for the rapid regulation of Na,K-ATPase activity. The apparent affinity of the ubiquitously expressed 1 isoform of the Na,K-ATPase catalytic subunit (1) for K + (K 1/2,K) is close to 1 mM, so that under physiological conditions of 4–5 mM of extracellular K + , acute regulation of its catalytic activity depends mainly on changes in the intracellular Na + concentration. 1 is the major iso-form in most cell types; in adult skeletal muscle, however, the Na,K-ATPase 2 isoform, which is the only iso-form present in the transverse tu-bules, predominates. Whereas 1 (localized to the sarcolemmal surface) mediates most of the basal Na + /K + transport required to maintain the gradients of these ions, 2 operates substantially below its maximum capacity in resting muscle, but is crucial to maintaining contraction and resisting fatigue in working muscle. Noting that the K + concentration in the restricted extracellular space of the transverse tubule lumen increases with muscle activity, in this issue DiFranco et al. measured activation of Na,K-ATPase current by external K + in voltage-clamped single mouse muscle fibers to determine the K + affinity of the 2 isoform. They determined that it was substantially lower than that of : rather than saturating at resting K + concentration, current increased with increasing K + at concentrations up to 40 mM. Thus, unlike 1, the activity of 2 was susceptible to acute stimulation by K + over the range of concentrations found in the transverse tubules of active muscle. The authors thus propose that the existence of two Na,K-ATPase  isoforms with distinct locations and differing K + affinities enables their preferential operation over the different ranges of extracellular K + concentrations characteristic of resting and active muscle, with 1 playing the major role at rest and 2 taking over as K + accumulates in the transverse tubules of working muscles. A cellular energy conduit Muscle cell function depends on the distribution of the potential energy generated …

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