Oral Presentation 2014 International Biophysics Congress

The cyclic-GMP-gated cationic conductance of the water channel Aquaporin-1 is important for rapid cell migration (#182)

Andrea Yool 1 , Jinxin Pei 1 , Michael De Ieso 1 , Mohamad Kourghi 1
  1. Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia

Cell migration is essential in development, regeneration, disease and protection. Polymerising actin filaments at leading edges generate the primary force. However, in highly motile cells, aquaporin-1 (AQP1) is localised in lamellipodia; upregulation is diagnostic of aggressive cancers including glioblastoma, breast and colon. Why don't other strong AQP water channels substitute for AQP1 in enhancing migration? One important difference is that AQP1 functions as a cation channel. The AQP1 conductance (~150 pS in physiological saline; PK=PCs~ PNa>PTEA>>PCa) shows slow gating kinetics, dependence on cGMP, little voltage sensitivity, and low open probability in heterologous expression systems suggesting additional regulation by pathways such as tyrosine phosphorylation (1,2,3). AQP1 ion channel activity has been replicated, but its physiological significance has remained controversial. We hypothesised the five-pore AQP1 channel (with individual water pores in each tetrameric subunit, and a central ion pore) is involved in dynamic volume regulation as exemplified during cell migration. Selective pharmacological modulators developed by our group are being used to evaluate the dependence of migration on water and cation channel activity in cancer cell lines which natively express AQP1. Dose-dependent modulators of AQP1 show no appreciable cross-talk with other channels and transporters. Migration is strongly stimulated by cGMP. Selective block of the AQP1 ion channel with a novel bumetanide derivative (AqB011) reverses the potentiating effect of cGMP, an effect mimicked by a non-selective AQP1 blocker Cd2+. New agents targeting migration and metastasis could be of substantial interest in cancer therapy.

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  2. Yool AJ (2007) Aquaporins: multiple roles in the central nervous system. Neuroscientist 13(5):470-485.
  3. Yool AJ and Campbell EM (2012) Structure, function and translational relevance of aquaporin dual water and ion channels. Mol Aspects Med 3(5-6):553-561.