Review
The role of volume-sensitive ion transport systems in regulation of epithelial transport

https://doi.org/10.1016/j.cbpa.2006.11.023Get rights and content

Abstract

This review focuses on using the knowledge on volume-sensitive transport systems in Ehrlich ascites tumour cells and NIH-3T3 cells to elucidate osmotic regulation of salt transport in epithelia. Using the intestine of the European eel (Anguilla anguilla) (an absorptive epithelium of the type described in the renal cortex thick ascending limb (cTAL)) we have focused on the role of swelling-activated K+- and anion-conductive pathways in response to hypotonicity, and on the role of the apical (luminal) Na+–K+–2Cl cotransporter (NKCC2) in the response to hypertonicity. The shrinkage-induced activation of NKCC2 involves an interaction between the cytoskeleton and protein phosphorylation events via PKC and myosin light chain kinase (MLCK). Killifish (Fundulus heteroclitus) opercular epithelium is a Cl-secreting epithelium of the type described in exocrine glands, having a CFTR channel on the apical side and the Na+/K+ATPase, NKCC1 and a K+ channel on the basolateral side. Osmotic control of Cl secretion across the operculum epithelium includes: (i) hyperosmotic shrinkage activation of NKCC1 via PKC, MLCK, p38, OSR1 and SPAK; (ii) deactivation of NKCC by hypotonic cell swelling and a protein phosphatase, and (iii) a protein tyrosine kinase acting on the focal adhesion kinase (FAK) to set levels of NKCC activity.

Introduction

Swelling-activated K+ and anion channels are important effectors during regulatory volume decrease (RVD after cell swelling, whereas a Na+, K+, 2Cl (NKCC) cotransporter and a Na+/H+ exchanger play major roles in the regulatory volume increase (RVI) following cell shrinkage. Transport pathways involved in RVD and RVI have been investigated in a wide variety of cell types (Hoffmann and Dunham, 1995, Lang et al., 1998, Wehner et al., 2003, Hoffmann and Pedersen, 2006). In the first part of this review we describe briefly the swelling activated channels and the shrinkage-activated NKCC and the signal transduction mechanisms involved in the activation of these transport systems by changes in cell volume. Other transport systems involved in rapid volume regulation and aspects of long-term adaptation to an anisosmotic environment are outside the scope of this review. In the second part of this review we will try to correlate this knowledge with the regulatory mechanisms involved in osmotic regulation of salt transport in epithelia using the killifish opercula epithelium and the eel intestinal epithelium as examples.

Section snippets

Swelling-activated K+ channels (IK,vol)

Swelling activation of a K+ leak pathway was initially established in lymphocytes (Roti Roti and Rothstein, 1973) and in Ehrlich ascites tumour cells (EATCs) (Hendil and Hoffmann, 1974). This swelling-activated increase in K+ permeability has been established in different cell types to be related to a variety of swelling-activated K+ channels including Ca2+-activated channels of small conductance (SK), intermediate conductance (IK) or large conductance (BK); stretch-activated K+ channels;

Osmosensing chloride-secreting cells of killifish opercular epithelium

The euryhaline killifish (or mummichog) Fundulus heteroclitus is known for its exceptional euryhalinity and can tolerate salinities ranging from freshwater (FW) to seawater (SW) to hypersaline conditions, as well as having the capacity to adapt quickly to large changes in salinity, such as direct FW-to-SW and reverse transfers. The killifish opercular epithelium and the skin of other euryhaline species, such as the goby (Gillichthys mirabilis) are rich in chloride cells; they provide useful

European eel intestine

The intestine of the euryhaline teleost European eel (Anguilla anguilla) is used as a model of a salt-absorbing epithelium; this epithelium is naturally, physiologically exposed to changes in extracellular osmolarity when the eel migrates from FW to SW and vice versa.

The ion transport model described for eel intestine is essentially identical to the model for the thick ascending limb(cTAL) of the mammalian renal cortex (Greger, 1985). NKCC2 in parallel with a K+ conductance is localized on the

Conclusions

It is well known that epithelial transport involving the entry or extrusion of osmotically active substances at the basolateral and apical cellular membranes represents a continuous challenge to epithelial cell volume regulation, because slight changes in the large apical or basolateral fluxes will lead to rapid changes in cell volume (Hoffmann and Ussing, 1992, Hoffmann and Dunham, 1995, Harvey, 1994, Beck et al., 1994). In addition, some epithelia can experience changes in extracellular

Acknowledgements

The work was supported by a James Chair visiting professorship to EKH, a grant from the Danish Network in Aquaculture and Fisheries research (www.fishnet.dk) and The Danish Natural Sciences Research Foundation to EKH, by M.I.U.R. grants Italy to TS, by a NSERC Canada grant to WSM.

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