A family of hyperpolarization-activated channels selective for protons

Wobig, Lea; Wolfenstetter, Thérèse; Fechner, Sylvia; Bönigk, Wolfgang; Körschen, Heinz G.; Jikeli, Jan F.; Trötschel, Christian; Feederle, Regina; Kaupp, U. Benjamin; Seifert, Reinhard; Berger, Thomas

doi:10.1073/pnas.2001214117

Cited by 13 publications

(11 citation statements)

References 51 publications

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“…Two functionally important variations are striking. First, herring sperm carry an HCN-like (HCNL) channel that is distinct from classic HCN channels and falls into a new gene subfamily ( 42 ). HCNL1 in zebrafish sperm, unlike classic HCN channels, is proton-selective and not cAMP-sensitive ( 42 ).…”

Section: Resultsmentioning

confidence: 99%

“…First, herring sperm carry an HCN-like (HCNL) channel that is distinct from classic HCN channels and falls into a new gene subfamily ( 42 ). HCNL1 in zebrafish sperm, unlike classic HCN channels, is proton-selective and not cAMP-sensitive ( 42 ). Although herring sperm carry the HCNL2 isoform that has not yet been characterized functionally, structural features underlying proton permeation are conserved between HCNL1 and HCNL2 ( 34 ).…”

Section: Resultsmentioning

confidence: 99%

“…Although herring sperm carry the HCNL2 isoform that has not yet been characterized functionally, structural features underlying proton permeation are conserved between HCNL1 and HCNL2 (34). Second, the zebrafish CNGK channel is also gated not by cyclic nucleotides but by alkaline pH i , indicating that the cellular messengers in fish sperm are protons rather than cAMP or cGMP (42,43). These results suggest that herring sperm employ a signaling pathway for fertilization that combines signaling proteins and mechanisms from marine invertebrates, zebrafish, and mammals.…”

Section: Catsper3y and Catsperg Are Essential Components Of The Herringmentioning

confidence: 99%

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Reconstruction of the birth of a male sex chromosome present in Atlantic herring

Rafati

Chen

Herpin

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The mechanisms underlying sex determination are astonishingly plastic. Particularly the triggers for the molecular machinery, which recalls either the male or female developmental program, are highly variable and have evolved independently and repeatedly. Fish show a huge variety of sex determination systems, including both genetic and environmental triggers. The advent of sex chromosomes is assumed to stabilize genetic sex determination. However, because sex chromosomes are notoriously cluttered with repetitive DNA and pseudogenes, the study of their evolution is hampered. Here we reconstruct the birth of a Y chromosome present in the Atlantic herring. The region is tiny (230 kb) and contains only three intact genes. The candidate male-determining gene BMPR1BBY encodes a truncated form of a BMP1B receptor, which originated by gene duplication and translocation and underwent rapid protein evolution. BMPR1BBY phosphorylates SMADs in the absence of ligand and thus has the potential to induce testis formation. The Y region also contains two genes encoding subunits of the sperm-specific Ca2+ channel CatSper required for male fertility. The herring Y chromosome conforms with a characteristic feature of many sex chromosomes, namely, suppressed recombination between a sex-determining factor and genes that are beneficial for the given sex. However, the herring Y differs from other sex chromosomes in that suppression of recombination is restricted to an ∼500-kb region harboring the male-specific and sex-associated regions. As a consequence, any degeneration on the herring Y chromosome is restricted to those genes located in the small region affected by suppressed recombination.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Catsper3y and Catsperg Are Essential Components Of The Herringmentioning

confidence: 99%

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Reconstruction of the birth of a male sex chromosome present in Atlantic herring

Rafati

Chen

Herpin

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Two major strategies have proved successful in developing ligands targeting the Hv1 VSD: one focused on the use of peptide toxins binding the channel extracellular side ( Alabi et al, 2007 ; Tang et al, 2020 ; Zhao et al, 2018 ) and the other focused on small organic molecules targeting the channel intracellular side ( Hong et al, 2014 ; Hong et al, 2013 ; Kalia and Swartz, 2013 ; Pupo and Gonzalez León, 2014 ). Some of these ligands have found applications as pharmacological tools to study the gating and permeation mechanisms of proton-conducting VSDs ( Chamberlin et al, 2014 ; Gianti et al, 2016 ; Hong et al, 2015 ; Qiu et al, 2013 ; Wobig et al, 2020 ) and the role of Hv1-mediated proton currents in cellular physiology ( Asuaje et al, 2017 ; Mészáros et al, 2020 ; Rennhack et al, 2017 ; Zhao et al, 2018 ). Drug-screening approaches on native proton currents or on other ion channels have led to the identification of additional potential ligands ( Kornilov et al, 2014 ; Shin et al, 2015 ; Shin and Song, 2014 ; Song et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD–ligand interactions

Zhao

Luan

Galpin

et al. 2021

Journal of General Physiology

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The human voltage-gated proton channel Hv1 is a drug target for cancer, ischemic stroke, and neuroinflammation. It resides on the plasma membrane and endocytic compartments of a variety of cell types, where it mediates outward proton movement and regulates the activity of NOX enzymes. Its voltage-sensing domain (VSD) contains a gated and proton-selective conduction pathway, which can be blocked by aromatic guanidine derivatives such as 2-guanidinobenzimidazole (2GBI). Mutation of Hv1 residue F150 to alanine (F150A) was previously found to increase 2GBI apparent binding affinity more than two orders of magnitude. Here, we explore the contribution of aromatic interactions between the inhibitor and the channel in the presence and absence of the F150A mutation, using a combination of electrophysiological recordings, classic mutagenesis, and site-specific incorporation of fluorinated phenylalanines via nonsense suppression methodology. Our data suggest that the increase in apparent binding affinity is due to a rearrangement of the binding site allowed by the smaller residue at position 150. We used this information to design new arginine mimics with improved affinity for the nonrearranged binding site of the wild-type channel. The new compounds, named “Hv1 Inhibitor Flexibles” (HIFs), consist of two “prongs,” an aminoimidazole ring, and an aromatic group connected by extended flexible linkers. Some HIF compounds display inhibitory properties that are superior to those of 2GBI, thus providing a promising scaffold for further development of high-affinity Hv1 inhibitors.

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“…Soluble AC and potential cAMP-signaling targets have also been identified in sperm of external fertilizers ranging from marine invertebrates to fish (7)(8)(9)(10)(11)(12). Although its properties seem to be conserved across phyla (7,13,14), the role of sAC in sperm exposed to aquatic habitats low in HCO3 -(2-4 mM) is enigmatic.…”

Section: Co2 + H2o ⇋ Hco3 -+ H +mentioning

confidence: 99%

External fertilization is orchestrated by a pH-regulated soluble adenylyl cyclase controlling sperm motility and chemotaxis

Hamzeh

Pascal

et al. 2021

Preprint

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The reaction of CO2 with H2O to form HCO3- and H+ is one of the most important chemical equilibria in cells. In mammalian sperm, a soluble adenylyl cyclase (sAC) serves as cellular HCO3- sensor that conveys the equilibrium state via cAMP synthesis to cAMP-signaling molecules. The function of sAC and cAMP in non-mammalian sperm is largely unknown. Here, we identify sAC orthologs in sea urchin and salmon sperm that, surprisingly, are activated by alkaline pH rather than HCO3-. Two amino-acid residues required for HCO3- binding of mammalian sAC are lacking in pH-regulated sAC. Orthologs identified in ten other phyla are also lacking either one of these key residues, suggesting that pH control is widespread among non-mammalian metazoan. The pH-sensitive sAC controls several functions of sperm from external fertilizers. Upon spawning, alkalization triggers cAMP synthesis and, thereby, activates motility of quiescent sperm. Egg-derived chemoattractants also alkalize sperm and elevate cAMP, which then-modulates pacemaker HCN channels to trigger a chemotactic Ca2+ response. Finally, the sAC and the voltage- and cAMP-activated Na+/H+ exchanger sNHE mutually control each other. A picture of evolutionary significance is emerging: motility and sensory signaling of sperm from both internal and external fertilizers rely on cAMP, yet, their sAC is regulated by HCO3- or pHi, respectively. Acidification of aquatic habitats due to climate change may adversely affect pH-sensing by sAC and thereby sexual reproduction in the sea.

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A family of hyperpolarization-activated channels selective for protons

Cited by 13 publications

References 51 publications

Reconstruction of the birth of a male sex chromosome present in Atlantic herring

Reconstruction of the birth of a male sex chromosome present in Atlantic herring

HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD–ligand interactions

External fertilization is orchestrated by a pH-regulated soluble adenylyl cyclase controlling sperm motility and chemotaxis

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