Voltage-Gated Proton Channels as Novel Drug Targets: From NADPH Oxidase Regulation to Sperm Biology.
CONCLUSIONS
Voltage-gated proton channels are increasingly implicated in cellular proton homeostasis. Proton currents were originally identified in snail neurons less than 40 years ago, and subsequently shown to play an important auxiliary role in the functioning of reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Molecular identification of voltage-gated proton channels was achieved less than 10 years ago. Interestingly, so far, only one gene coding for voltage-gated proton channels has been identified, namely hydrogen voltage-gated channel 1 (HVCN1), which codes for the HV1 proton channel protein. Over the last years, the first picture of putative physiological functions of HV1 has been emerging.


BACKGROUND
The best-studied role remains charge and pH compensation during the respiratory burst of the phagocyte NADPH oxidase (NOX). Strong evidence for a role of HV1 is also emerging in sperm biology, but the relationship with the sperm NOX5 remains unclear. Probably in many instances, HV1 functions independently of NOX: for example in snail neurons, basophils, osteoclasts, and cancer cells.


RESULTS
Generally, ion channels are good drug targets; however, this feature has so far not been exploited for HV1, and hitherto no inhibitors compatible with clinical use exist. However, there are emerging indications for HV1 inhibitors, ranging from diseases with a strong activation of the phagocyte NOX (e.g., stroke) to infertility, osteoporosis, and cancer.


CONCLUSIONS
Clinically useful HV1-active drugs should be developed and might become interesting drugs of the future.
1 Department of Pathology and Immunology, Geneva University Medical Faculty , Centre Médical Universitaire, Geneva, Switzerland .
Tamara
T
Seredenina
2 Department of Cellular Physiology and Metabolism, Geneva University Medical Faculty , Centre Médical Universitaire, Geneva, Switzerland .
Nicolas
N
Demaurex
1 Department of Pathology and Immunology, Geneva University Medical Faculty , Centre Médical Universitaire, Geneva, Switzerland .|3 Department of Genetic and Laboratory Medicine, Geneva University Hospitals , Centre Médical Universitaire, Geneva, Switzerland .
Karl-Heinz
KH
Krause
D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D013094:Spermatozoa / Q000378:metabolism*
D062565:Acid Sensing Ion Channels; C510235:HVCN1 protein, human; D007473:Ion Channels; D019255:NADPH Oxidases