Differential Inhibition of T-Type Calcium Channels by Neuroleptics

Salomonsson

et al. 2004

British J Pharmacology

In this study, intracellular Ca2+ was measured as the Fura‐2 ratio (R) of fluorescence excited at 340 and 380 nm (F340/F380) in nonpressurized rat mesenteric small arterioles (Ø (lumen diameter) 10–25 μm). The response to depolarization using 75 mM KCl was an increase in R from a baseline of 0.96±0.01 ([Ca2+]i ∼74 nM) to 1.04±0.01 (∼128 nM) (n=80). The response to 75 mM K+ was reversibly abolished in Ca2+‐free physiological saline solution, whereas phentolamine (10 μM) or tetrodotoxin (1 μM) had no effects. LaCl3 (200 μM) inhibited 61±9% of the response. A [K+]‐response curve indicated that the Ca2+ response was activated between 15 and 25 mM K+. The data suggest that the Ca2+ response was caused by the activation of voltage‐dependent Ca2+ channels. Mibefradil use dependently inhibited the Ca2+ response to 75 mM K+ by 29±2% (100 nM), 73±7% (1 μM) or 89±7% (10 μM). Pimozide (500 nM) use dependently inhibited the Ca2+ response by 85±1%. Nifedipine (1 μM) inhibited the Ca2+ response to 75 mM K+ by 41±12%. The response was not inhibited by calciseptine (500 nM), ω‐agatoxin IVA (100 nM), ω‐conotoxin MVIIA (500 nM), or SNX‐482 (100 nM). Using reverse transcriptase–polymerase chain reaction, it was shown that neither CaV2.1a (P‐type) nor CaV2.1b (Q‐type) voltage‐dependent Ca2+ channels were expressed in mesenteric arterioles, whereas the CaV3.1 (T‐type) channel was expressed. Furthermore, no amplification products were detected when using specific primers for the β1b, β2, or β3 auxiliary subunits of high‐voltage‐activated Ca2+ channels. The results suggest that the voltage‐dependent Ca2+ channel activated by sustained depolarization in mesenteric arterioles does not classify as any of the high‐voltage‐activated channels (L‐, P/Q‐, N‐, or R‐type), but is likely to be a T‐type channel. The possibility that the sustained Ca2+ influx observed was the result of a T‐type window current is discussed. British Journal of Pharmacology (2004) 142, 709–718. doi:10.1038/sj.bjp.0705841

Section: Lj Jensen Et Almentioning

confidence: 99%

Depolarization‐induced calcium influx in rat mesenteric small arterioles is mediated exclusively via mibefradil‐sensitive calcium channels

Salomonsson

et al. 2004

British J Pharmacology

“…Clinically, flunarizine is known as Sibeliumt and has been widely used to treat the clinical disorders, including vertigo, migraine, epilepsy, and tinnitus. 12 Recently, it is known to protect the perfused rat liver cells from ischemia with reperfusion and neurons from serum deprivation, nerve growth factor deprivation, oxidative stress, and axotomy, respectively. 13 Previously, we reported that flunarizine attenuated the cisplatin-induced apoptosis of auditory cells through inhibition of lipid peroxidation and mitochondrial permeability transition.…”

Section: Introductionmentioning

confidence: 99%

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Kim

et al. 2006

Cell Death Differ

We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GSTl-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.

“…The majority of drug binding sites that have been characterized surround the channel pore, involving the fifth and sixth transmembrane helices, or they lie within the permeation pathway (reference 35 and references therein). Although there is no structural information regarding the precise binding site of flunarizine, it is well established that this neuroleptic is used to treat migraine (36) and vertigo (37) and that it inhibits all three T-type Ca 2ϩ channels (38). Moreover, a moderate antagonistic activity toward dopamine receptors was reported (38).…”

Section: Ion Channel Inhibitors and Related Antihistamines As First-imentioning

confidence: 99%

“…Although there is no structural information regarding the precise binding site of flunarizine, it is well established that this neuroleptic is used to treat migraine (36) and vertigo (37) and that it inhibits all three T-type Ca 2ϩ channels (38). Moreover, a moderate antagonistic activity toward dopamine receptors was reported (38). Thus, all of the abovementioned drugs have in common the fact that they inhibit cellular transmembrane proteins with multiple transmembrane helices.…”

Section: Ion Channel Inhibitors and Related Antihistamines As First-imentioning

confidence: 99%

“…Along the same lines, dopamine receptors and T-type Ca 2ϩ ion channels (CACNA1G, CACNA1H, CACNA1I) are not (or are poorly) expressed in Huh-7.5 cells (Ͻ0.18 reads per kilobase per million [RPKM]) (data not shown; T. Pietschmann, unpublished observation), in primary hepatocyte transcriptional profiles, and in human livers (the Human Protein Atlas [http://www.proteinatlas.org]). Moreover, pimozide inhibits T-type Ca 2ϩ channels much more effectively than flunarizine (38) but inhibits HCV about as much as flunarizine (7). Beyond this, other potent Ca 2ϩ channel inhibitors, like mibefradil (41), penfluridol (42), and NiCl 2 (43), do not inhibit HCV, and chelation of intracellular or extracellular Ca 2ϩ does not influence the antiviral activity of flunarizine (7).…”

Section: Ion Channel Inhibitors and Related Antihistamines As First-imentioning

confidence: 99%

See 1 more Smart Citation

Clinically Approved Ion Channel Inhibitors Close Gates for Hepatitis C Virus and Open Doors for Drug Repurposing in Infectious Viral Diseases

Pietschmann

2017

J Virol

Chronic hepatitis C virus (HCV) infection causes severe liver disease and affects ca. 146 million individuals. Novel directly acting antivirals targeting HCV have revolutionized treatment. However, high costs limit access to therapy. Recently, several related drugs used in humans to treat allergies or as neuroleptics emerged as potent HCV cell entry inhibitors. Insights into their antiviral modes of action may increase opportunities for drug repurposing in hepatitis C and possibly other important human viral infections.