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: 5.04). 12/2000; 528(Pt 3):457-72. DOI: 10.1111/j.1469-7793.2000.00457.x
Source: PubMed


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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    ABSTRACT: The CNS is particularly vulnerable to reductions in plasma osmolarity, such as occur during hyponatremia, the most commonly encountered electrolyte disorder in clinical practice. In response to a lowered plasma osmolarity, neural cells initially swell but then are able to restore their original volume through the release of osmolytes, both inorganic and organic, and the exit of osmotically obligated water. Given the importance of the maintenance of cell volume within the CNS, mechanisms underlying the release of osmolytes assume major significance. In this context, we review recent evidence obtained from our laboratory and others that indicates that the activation of specific G-protein-coupled receptors can markedly enhance the volume-dependent release of osmolytes from neural cells. Of particular significance is the observation that receptor activation significantly lowers the osmotic threshold at which osmolyte release occurs, thereby facilitating the ability of the cells to respond to small, more physiologically relevant, reductions in osmolarity. The mechanisms underlying G-protein-coupled receptor-mediated osmolyte release and the possibility that this efflux can result in both physiologically beneficial and potentially harmful pathophysiological consequences are discussed.
    Journal of Neurochemistry 09/2008; 106(5):1998-2014. DOI:10.1111/j.1471-4159.2008.05510.x · 4.28 Impact Factor
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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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    ABSTRACT: Cancer is caused by defects in the mechanisms underlying cell proliferation and cell death. Calcium ions are central to both phenomena, serving as major signalling agents with spatial localization, magnitude and temporal characteristics of calcium signals ultimately determining cell's fate. There are four primary compartments: extracellular space, cytoplasm, endoplasmic reticulum and mitochondria that participate in the cellular Ca2+ circulation. They are separated by own membranes incorporating divers Ca2(+)-handling proteins whose concerted action provides for Ca2+ signals with the spatial and temporal characteristics necessary to account for specific cellular response. The transformation of a normal cell into a cancer cell is associated with a major re-arrangement of Ca2+ pumps, Na/Ca exchangers and Ca2+ channels, which leads to the enhanced proliferation and impaired ability to die. In the present chapter we examine what changes in Ca+ signalling and the mechanisms that support it underlie the passage from normal to pathological cell growth and death control. Understanding this changes and identifying molecular players involved provides new prospects for cancers treatment.
    Sub-cellular biochemistry 02/2007; 45:405-27. DOI:10.1007/978-1-4020-6191-2_15
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