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Cardiovascular Research 2007 73(1):92-100; doi:10.1016/j.cardiores.2006.11.006
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Copyright © 2006, European Society of Cardiology

Differential distribution and regulation of mouse cardiac Na+/K+-ATPase {alpha}1 and {alpha}2 subunits in T-tubule and surface sarcolemmal membranes

Roger G. Berrya, Sanda Despab, William Fullera, Donald M. Bersb and Michael J. Shattocka,*

aCardiac Physiology, King's College London, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK
bDepartment of Physiology, Loyola University Chicago, Maywood, Illinois, USA

* Corresponding author. Tel.: +44 20 7188 0945; fax: +44 20 7188 3902. Email address: michael.shattock{at}kcl.ac.uk

Objectives: Two Na+/K+-ATPase (NKA) {alpha}-subunit isoforms, {alpha}1 and {alpha}2, are expressed in the adult mouse heart. The subcellular distribution of these isoforms in T-tubule and surface sarcolemmal (SSL) membranes and their regulation by cAMP-dependent protein kinase (PKA) is unclear.

Methods: We used formamide-induced detubulation of mouse ventricular myocytes to investigate differential functional distribution and regulation by PKA of {alpha}1 and {alpha}2 in T-tubule versus SSL membranes by measuring NKA current (Ipump) and NKA-mediated Na+ efflux (–d[Na]i/dt).

Results: Ipump is composed of 88% {alpha}1-mediated Ipump (I{alpha}1) and 12% {alpha}2-mediated Ipump (I{alpha}2). {alpha}1 and {alpha}2 subunits demonstrate distinct ouabain affinities (105±6 and 0.3±0.1 µmol/L respectively) but similar affinity for intracellular Na+ (K1/2Na+ of 16.6±0.8 and 16.7±2.6 mmol/L respectively). Detubulation reduced (i) Ipump density (1.42±0.1 to 1.20±0.04 pA/pF), (ii) cell capacitance (181±12 to 127±17 pF), and (iii) I{alpha}2 contribution (12 to 6%). Total Ipump density was ~60% higher in T-tubule (1.94 pA/pF, derived) vs. SSL membranes. Although T-tubule membranes represent only 30% of total surface area, they generate ~70% of I{alpha}2 and ~37% of I{alpha}1. I{alpha}1 density was substantially higher than I{alpha}2 in SSL (I{alpha}1:I{alpha}2=16:1) but this was markedly reduced in T-tubules (4:1). In addition to differential localisation, isoprenaline (ISO, 1 µmol/L) significantly increased {alpha}1-mediated NKA Na+ affinity (from 16.6±0.8 to 13.3±1.4 mmol/L) and caused a small increase in maximal NKA Na+ efflux rate. ISO had no effect on {alpha}2-mediated NKA activity.

Conclusion: These data suggest that NKA {alpha}1 and {alpha}2 subunits are differentially localised and regulated by PKA in T-tubule and SSL membranes and may have distinct regulatory roles in cardiac excitation–contraction coupling.

KEYWORDS Ion pumps; Na/K-pump; Sarcolemmal; Protein kinase A; Adrenergic agonist

Time for primary review 39 days


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