Article

Ca 2+-sensing receptor-mediated regulation of volume-sensitive Cl - channels in human epithelial cells

Department of Cell Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
The Journal of Physiology (Impact Factor: 4.54). 12/2000; 528(Pt 3):457-72. DOI: 10.1111/j.1469-7793.2000.00457.x
Source: PubMed

ABSTRACT Since extracellular Ca2+ or Mg2+ has been reported to modulate swelling-activated Cl- currents, we examined the expression of the G protein-coupled Ca2+-sensing receptor (CaR) and its involvement in the regulation of volume-sensitive Cl- channels in a human epithelial cell line (Intestine 407). Reverse transcriptase-polymerase chain reaction and immunoblotting analysis showed that Intestine 407 cells express CaR mRNA and protein. The swelling-activated whole-cell Cl- current was voltage-independently augmented by extracellular Ca2+ or Mg2+. In addition, Ca2+ or Mg2+ voltage-dependently accelerated the inactivation kinetics of the Cl- current. Neomycin, spermine and La3+ augmented volume-sensitive Cl- currents. However, these CaR agonists failed to affect depolarization-induced inactivation. Intracellular application of GTPgammaS, but not GDPbeta]S, increased the amplitude of the swelling-induced Cl- current without affecting the basal current. The upregulating effect of Ca2+ on the Cl- current amplitude was abolished by either GTPgammaS or GDPbetaS. In contrast, GTPgammaS and GDPbetaS failed to affect the inactivation kinetics of the Cl- current and the accelerating effect of Ca2+ thereon. The Cl- current amplitude was enlarged by stimulation with forskolin, dibutyryl cAMP and IBMX. During the cAMP stimulation, extracellular Ca2+ failed to increase the Cl- current but did accelerate depolarization-induced inactivation. It is concluded that stimulation of the CaR induces upregulation of volume-sensitive Cl- channels via a G protein-mediated increase in intracellular cAMP in the human epithelial cell. However, the accelerating effect of extracellular divalent cations on the inactivation kinetics of the Cl- current is induced by a mechanism independent of the CaR and cAMP.

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    • "Although non-receptor-mediated increases in cAMP have been reported to facilitate osmolyte efflux or swelling-activated Cl -current in several tissues (Strange et al. 1993; Shimizu et al. 2000; Moran et al. 2001), there are currently only three documented examples of the ability of cyclase-linked GPCRs to enhance volume-dependent osmolyte release. Thus norepinephrine, acting via a β-adrenergic receptor, has been reported to increase taurine release from flounder erythrocytes and cortical astrocytes (Thoroed et al. 1995; Moran et al. 2001). "
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    • "CaSR may also influence the proliferative and apoptotic status of the cells indirectly via modulation of cell volume homeostasis. Indeed, stimulation of CaSR in human epithelial cells induces upregulation of volume-regulated anion channels (VRAC) via a G protein-mediated increase in intracellular cAMP (Shimizu, et al., 2000). Proliferation and apoptosis are associated with essential volume perturbations [e.g., (Lang, et al., 2000)] and VRAC, a key component of homeostatic volume regulation, has been directly implicated in proliferation (Chen, et al., 2002, Doroshenko, et al., 2001, Shen, et al., 2000, Wang, et al., 2002) and apoptosis (Lemonnier, et al., 2004, Okada, et al., 2001, Okada, et al., 2006, Shen, et al., 2002). "
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