Fendiline increases [Ca2+]i in Madin Darby canine kidney (MDCK) cells by releasing internal Ca2+ followed by capacitative Ca2+ entry

Jan, Chung‐Ren; Tseng, Ching‐Jiunn; Chen, Wei‐Chuan

doi:10.1016/s0024-3205(99)00670-0

Cited by 15 publications

(14 citation statements)

References 21 publications

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“…Fendiline was recently reported to increase [Ca 2+ ] i in a renal tubular cell line [Madin Darby canine kidney (MDCK) cells] by releasing internal Ca 2+ and activating external Ca 2+ influx [9]. The effect of fendiline found in the present study was similar to that found in MDCK cells except for one major difference.…”

Section: Discussionsupporting

confidence: 83%

“…In vitro, fendiline has been found to inhibit L-type Ca 2+ channels [6,7] and calmodulin [8]. Notably, fendiline was recently shown to act as a Ca 2+ mobilizer in renal tubular cells, by releasing stored Ca 2+ and activating external Ca 2+ influx [9]. Thus, in an attempt to search for new anti-bladder cancer drugs, in the present study, the effect of fendiline on [Ca 2+ ] i in human bladder female transitional carcinoma (BFTC) cells was examined.…”

Section: Introductionmentioning

confidence: 99%

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Dual Effect of the Antianginal Drug Fendiline on Bladder Female Transitional Carcinoma Cells: Mobilization of Intracellular Ca2+ and Induction of Cell Death

Jan

Huang

2001

Pharmacology

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The effect of fendiline, an antianginal drug, on cytosolic free Ca²⁺ levels ([Ca²⁺]_i) in populations of bladder female transitional carcinoma (BFTC) cells was explored using fura-2 as a Ca²⁺ indicator. Fendiline at concentrations between 3 and 200 µmol/l increased [Ca²⁺]_i in a concentration-dependent manner and the signal saturated at 100 µmol/l. The [Ca²⁺]_i signal was biphasic, with an initial rise and a slow decay. Ca²⁺ removal inhibited the Ca²⁺ signal by about half in peak amplitude. Adding 3 mmol/l Ca²⁺ increased [Ca²⁺]_i in cells pretreated with 100 µmol/l fendiline in Ca²⁺-free medium, suggesting that fendiline induced Ca²⁺ influx via capacitative Ca²⁺ entry. In Ca²⁺-free medium, pretreatment with 1 µmol/l thapsigargin (an endoplasmic reticulum Ca²⁺ pump inhibitor) to deplete the endoplasmic reticulum Ca²⁺ store inhibited most of the 100 µmol/l fendiline-induced internal Ca²⁺ release; and conversely, pretreatment with 100 µmol/l fendiline partly inhibited 1 µmol/l thapsigargin-induced Ca²⁺ release. This indicates that the major internal Ca²⁺ store of fendiline-induced [Ca²⁺]_i increases is located in the endoplasmic reticulum. The Ca²⁺ release induced by 100 µmol/l fendiline may be partly mediated by inositol 1,4,5-trisphosphate, because the [Ca²⁺]_i increase was inhibited by 50% by inhibiting phospholipase C with 2 µmol/l U73122. Fendiline (100 µmol/l) decreased cell viability by 12–44% after being added to cells for 2– 30 min. Together, the findings indicate that in BFTC cells, fendiline exerts a dual effect: mobilization of intracellular Ca²⁺ and induction of cell death.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Dual Effect of the Antianginal Drug Fendiline on Bladder Female Transitional Carcinoma Cells: Mobilization of Intracellular Ca2+ and Induction of Cell Death

Jan

Huang

2001

Pharmacology

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“…Maximum and minimum fluorescence values were obtained by adding 0.1% Triton X-100 and 20 m M EGTA sequentially at the end of each experiment. [Ca 2+ ] i was calculated as described previously [13, 14]. …”

Section: Methodsmentioning

confidence: 99%

Clomiphene, an Ovulation-Inducing Agent, Mobilizes Intracellular Ca2+ and Causes Extracellular Ca2+ Influx in Bladder Female Transitional Carcinoma Cells

Jan¹,

Huang

2000

Horm Res Paediatr

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Background/Methods: The effect of clomiphene, an ovulation-inducing agent, on cytosolic free Ca²⁺ levels ([Ca²⁺]_i) in populations of BFTC human bladder cancer cells was explored by using fura-2 as a Ca²⁺ indicator. Results: Clomiphene at concentrations between 10 and 75 µM increased [Ca²⁺]_i in a concentration-dependent manner and the signal saturated at 50 µM. The [Ca²⁺]_i signal was biphasic with an initial rise and a slow decay. Ca²⁺ removal inhibited the Ca²⁺ signal by about 40–50% in maximum [Ca²⁺]_i. Adding 3 mM Ca²⁺ increased [Ca²⁺]_i in cells pretreated with 50 µM clomiphene in Ca²⁺-free medium, suggesting that clomiphene induced capacitative Ca²⁺ entry. In Ca²⁺-free medium, pretreatment with 50 µM brefeldin A (to disrupt the Golgi complex Ca²⁺ store), 1 µM thapsigargin (to inhibit the endoplasmic reticulum Ca²⁺ pump), and CCCP (to uncouple mitochondria) inhibited 85% of clomiphene-induced intracellular Ca²⁺ release. Conversely, pretreatment with 50 µM clomiphene in Ca²⁺-free medium abolished the [Ca²⁺]_i increase induced by brefeldin, thapsigargin or CCCP. The intracellular Ca²⁺ release was unaltered by inhibiting formation of inositol-1,4,5-trisphosphate (IP₃) with 2 mM 1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122; a phospholipase C inhibitor). Conclusion: The [Ca²⁺]_i increase induced by 50 µM clomiphene was not affected by 10 µM of nifedipine, verapamil or diltiazem. Collectively, the results suggest that clomiphene releases intracellular Ca²⁺ in an IP₃-independent manner and also activates extracellular Ca²⁺ influx.

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“…At the cellular level, fendiline inhibits L-type calcium channels in muscle cells in vitro (64,93) and has an inhibitory effect on the calciumsensing protein calmodulin (55,69). Most importantly, it was shown to act as a calcium mobilizer in renal tubular cells, by releasing stored calcium and activating extracellular calcium entry (41). Originally, it was found to be an anti-anginal drug used in the treatment of coronary heart disease (5), but subsequently its ability to increase intracellular calcium by an allosteric modulatory action at extracellular CaSRs has been discovered.…”

Section: Pharmacologymentioning

confidence: 99%

Clinical Potential of GABA_B Receptor Modulators

Ong

Kerr

2005

CNS Drug Reviews

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Metabotropic gamma-aminobutyric acid(B) (GABAB) receptors for the major inhibitory transmitter GABA, together with metabotropic glutamate (mGLuRs) receptors, the extracellular calcium-sensing receptors (CaSRs), some V2R pheromone receptors and T1R taste receptors, belong to the family of 3 G-protein-coupled receptors (GPCRs). GABAB receptors are known to control neuronal excitability and modulate synaptic neurotransmission, playing a very important role in many physiological activities. These receptors are widely expressed and distributed in the nervous system and have been implicated in a variety of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, depression, schizophrenia and drug addiction. To form a functional receptor entity, GABAB receptors must exist as a heterodimer consisting of GABAB1 and GABAB2 receptor subtypes with two 7-transmembrane proteins, and these subunits arise from distinct genes. The GABAB1 subunit binds the endogenous ligand within its extracellular N-terminus, whilst the GABAB2 subunit is not only essential for the correct trafficking of the GABAB1 subunit to the cell surface, but is also responsible for the interaction of the receptor with its cognate G-protein. Allosteric modulation has recently been recognized as an alternative pharmacological approach to gain selectivity in drug action. It is now generally accepted that modulators acting at the allosteric sites provide a novel perspective for the development of subtype-selective agents acting at GPCRs. These agents interact with allosteric binding sites quite separate from the highly conserved agonist binding region. In this review, we present a new class of phenylalkylamines, based on the lead compound fendiline, that are potent positive potentiators of GABAB receptor-mediated function and discuss their putative clinical applications. It is proposed that these new modulators may have therapeutic value in GABAB receptor pharmacology and are capable of selectively modifying GABAB receptor function. The allosteric modulators are offering an attractive and novel means to identify new leads, that are devoid of side effects associated with GABAB receptor agonists, and may, therefore, represent a major advance in the drug discovery process.

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Fendiline increases [Ca2+]i in Madin Darby canine kidney (MDCK) cells by releasing internal Ca2+ followed by capacitative Ca2+ entry

Cited by 15 publications

References 21 publications

Dual Effect of the Antianginal Drug Fendiline on Bladder Female Transitional Carcinoma Cells: Mobilization of Intracellular Ca<sup>2+</sup> and Induction of Cell Death

Dual Effect of the Antianginal Drug Fendiline on Bladder Female Transitional Carcinoma Cells: Mobilization of Intracellular Ca<sup>2+</sup> and Induction of Cell Death

Clomiphene, an Ovulation-Inducing Agent, Mobilizes Intracellular Ca<sup>2+</sup> and Causes Extracellular Ca<sup>2+</sup> Influx in Bladder Female Transitional Carcinoma Cells

Clinical Potential of GABA_B Receptor Modulators

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Fendiline increases [Ca2+]i in Madin Darby canine kidney (MDCK) cells by releasing internal Ca2+ followed by capacitative Ca2+ entry

Cited by 15 publications

References 21 publications

Dual Effect of the Antianginal Drug Fendiline on Bladder Female Transitional Carcinoma Cells: Mobilization of Intracellular Ca<sup>2+</sup> and Induction of Cell Death

Dual Effect of the Antianginal Drug Fendiline on Bladder Female Transitional Carcinoma Cells: Mobilization of Intracellular Ca<sup>2+</sup> and Induction of Cell Death

Clomiphene, an Ovulation-Inducing Agent, Mobilizes Intracellular Ca<sup>2+</sup> and Causes Extracellular Ca<sup>2+</sup> Influx in Bladder Female Transitional Carcinoma Cells

Clinical Potential of GABAB Receptor Modulators

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Clinical Potential of GABA_B Receptor Modulators