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© The Rockefeller University Press, 0022-1295/1997//327/ $5.00
Journal of General Physiology, Volume 110, Number 3, 1997

Article

Activation of Na+-permeant Cation Channel by Stretch and Cyclic AMP-dependent Phosphorylation in Renal Epithelial A6 Cells

Yoshinori Marunaka*,§, Yutaka Shintani*,§, Gregory P. Downey{ddagger},||, and Naomi Niisato*,§

From the * Laboratory for Cellular and Molecular Physiology, Division of Respiratory Research, Hospital for Sick Children Research Institute, {ddagger} Division of Respirology, Department of Medicine, The Toronto Hospital, § Department of Paediatrics, and || Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1X8

It is currently believed that a nonselective cation (NSC) channel, which responds to arginine vasotocin (an antidiuretic hormone) and stretch, regulates Na+ absorption in the distal nephron. However, the mechanisms of regulation of this channel remain incompletely characterized. To study the mechanisms of regulation of this channel, we used renal epithelial cells (A6) cultured on permeable supports. The apical membrane of confluent monolayers of A6 cells expressed a 29-pS channel, which was activated by stretch or by 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterase. This channel had an identical selectivity for Na+, K+, Li+, and Cs+, but little selectivity for Ca2+ (PCa/PNa < 0.005) or Cl– (PCl/PNa < 0.01), identifying it as an NSC channel. Stretch had no additional effects on the open probability (Po) of the IBMX-activated channel. This channel had one open ("O") and two closed (short "CS" and long "CL") states under basal, stretch-, or IBMX-stimulated conditions. Both stretch and IBMX increased the Po of the channel without any detectable changes in the mean open or closed times. These observations led us to the conclusion that a kinetic model "CL {leftrightarrow} CS {leftrightarrow} O" was the most suitable among three possible linear models. According to this model, IBMX or stretch would decrease the leaving rate of the channel for CL from CS, resulting in an increase in Po. Cytochalasin D pretreatment abolished the response to stretch or IBMX without altering the basal activity. H89 (an inhibitor of cAMP-dependent protein kinase) completely abolished the response to both stretch and IBMX, but, unlike cytochalasin D, also diminished the basal activity. We conclude that: (a) the functional properties of the cAMP-activated NSC channel are similar to those of the stretch-activated one, (b) the actin cytoskeleton plays a crucial role in the activation of the NSC channel induced by stretch and cAMP, and (c) the basal activity of the NSC channel is maintained by PKA-dependent phosphorylation but is not dependent on actin microfilaments.

Key Words: nonselective cation channel • single channel • cytochalasin D • cyclic AMP • actin filament

Address correspondence to Dr. Yoshinori Marunaka, Division of Respiratory Research, Hospital for Sick Children Research Institute, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Fax: 416-813-5771; E-mail: marunaka{at}sickkids.on.ca


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