Dielectrophoretic analysis of changes in cytoplasmic ion levels due to ion channel blocker action reveals underlying differences between drug-sensitive and multidrug-resistant leukaemic cells

Abstract The fertility potential of human sperm populations can be assessed by the presence of head-directed mannose ligand receptors (mannose-specific lectin) and the occurrence of spontaneous acrosome reactions after incubation under capacitating conditions in vitro. We have reported previously on the interaction between anti-hypertensive medications and their effects on these parameters of male fertility potential. In this report we document the effects of cessation of calcium ion channel blocker medication on male fertility. Motile spermatozoa from a 30 year old infertile patient on a calcium ion channel blocker as anti-hypertensive treatment had subnormal expression of mannose-specific lectin and did not exhibit spontaneous acrosome reactions. Three months following discontinuation of the medications, complete recovery of both the expression of head-directed mannose ligand receptors and the acrosome reaction was documented, though sperm motility and morphology remained unchanged. The couple had 2 years of infertility and previously failed to conceive through seven cycles of Pergonal/intra-uterine insemination. Conception occurred on the second Pergonal/intra-uterine insemination cycle after the husband discontinued calcium ion channel blocker medication. Calcium ion channel blockers may adversely affect sperm fertilizing potential. Discontinuation of such medications enhances the chances for conception.

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In Silico Predictions and In Vivo Results of Drug-Drug Interactions by Ketoconazole and Verapamil on AZD1305, a Combined Ion Channel Blocker and a Sensitive CYP3A4 Substrate

Clinical Pharmacology in Drug Development ◽

10.1002/cpdd.250 ◽

2016 ◽

Vol 5 (5) ◽

pp. 364-373 ◽

Cited By ~ 3

Author(s):

Susanne Johansson ◽

Boel Löfberg ◽

Maria Aunes ◽

Helen Lunde ◽

Lars Frison ◽

...

Keyword(s):

Drug Interactions ◽

Ion Channel ◽

In Silico ◽

Channel Blocker ◽

Cyp3a4 Substrate ◽

In Silico Predictions

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Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole

Nature Communications ◽

10.1038/s41467-021-26608-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Arthur Neuberger ◽

Kirill D. Nadezhdin ◽

Alexander I. Sobolevsky

Keyword(s):

Ion Channel ◽

Conformational Changes ◽

Calcium Imaging ◽

Molecular Mechanisms ◽

Channel Blocker ◽

Ruthenium Red ◽

Allosteric Site ◽

Structural Mechanisms ◽

New Generation ◽

Molecular Bases

AbstractTRPV6 is a calcium-selective ion channel implicated in epithelial Ca2+ uptake. TRPV6 inhibitors are needed for the treatment of a broad range of diseases associated with disturbed calcium homeostasis, including cancers. Here we combine cryo-EM, calcium imaging, and mutagenesis to explore molecular bases of human TRPV6 inhibition by the antifungal drug econazole and the universal ion channel blocker ruthenium red (RR). Econazole binds to an allosteric site at the channel’s periphery, where it replaces a lipid. In contrast, RR inhibits TRPV6 by binding in the middle of the ion channel’s selectivity filter and plugging its pore like a bottle cork. Despite different binding site locations, both inhibitors induce similar conformational changes in the channel resulting in closure of the gate formed by S6 helices bundle crossing. The uncovered molecular mechanisms of TRPV6 inhibition can guide the design of a new generation of clinically useful inhibitors.

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