Mice lacking the proton channel Hv1 exhibit sex-specific differences in glucose homeostasis

Pang, Huimin; Li, Jinzhi; Wang, Yuzhou; Su, Xiaomin; Gao, Yingtang; Li, Shu Jie

doi:10.1016/j.jbc.2021.101212

Cited by 5 publications

(4 citation statements)

References 43 publications

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“…Female mice had lower glucose at fasting and throughout GTT compared to male mice ( Figure 1 ). This is consistent with some past work ( 9 , 10 , 23 ) but not all ( 24 ). We show that LPS administration improved glucose tolerance in all mice, across sex and genotype ( Figure 2 ).…”

Section: Discussionsupporting

confidence: 93%

Sex-specific effect of P2Y2 purinergic receptor on glucose metabolism during acute inflammation

Ulbricht,

Rivas,

Marino

et al. 2023

Front. Endocrinol.

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The sex of an animal impacts glucose sensitivity, but little information is available regarding the mechanisms causing that difference, especially during acute inflammation. We examined sex-specific differences in the role of the P2Y2 receptor (P2Y2R) in glucose flux with and without LPS challenge. Male and female wild-type and P2Y2R knockout mice (P2Y2R-/-) were injected with LPS or saline and glucose tolerance tests (GTT) were performed. P2Y2R, insulin receptor, and GLUT4 transporter gene expression was also evaluated. Female mice had reduced fasting plasma glucose and females had reduced glucose excursion times compared to male mice during GTT. P2Y2R-/- males had significantly decreased glucose flux throughout the GTT as compared to all female mice. Acute inflammation reduced fasting plasma glucose and the GTT area under the curve in both sexes. While both wild-type and P2Y2R-/- male animals displayed reduced fasting glucose in LPS treatment, female mice did not have significant difference in glucose tolerance, suggesting that the effects of P2Y2R are specific to male mice, even under inflammatory conditions. Overall, we conclude that the role for the purinergic receptor, P2Y2R, in regulating glucose metabolism is minimal in females but plays a large role in male mice, particularly in the acute inflammatory state.

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Section: Discussionsupporting

confidence: 93%

Sex-specific effect of P2Y2 purinergic receptor on glucose metabolism during acute inflammation

Ulbricht,

Rivas,

Marino

et al. 2023

Front. Endocrinol.

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“…In humans, a higher hHv1 expression/function has been reported in several types of cancer cells such as breast cancer, , colorectal cancer, glioblastoma, and B-cell leukemia, whereas a loss of function seems to be involved in male infertility. − On the other hand, working on the Hv1 KO mice, there is evidence that Hv1 inhibition protects the neuroinflammation induced by cerebral ischemic stroke , and induces several alterations in glucose metabolism. , …”

Section: Introductionmentioning

confidence: 99%

Novel Dimeric hHv1 Model and Structural Bioinformatic Analysis Reveal an ATP-Binding Site Resulting in a Channel Activating Effect

Llanos

Ventura

Martín

et al. 2022

J. Chem. Inf. Model.

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The human voltage-gated proton channel (hHv1) is a highly selective ion channel codified by the HVCN1 gene. It plays a fundamental role in several physiological processes such as innate and adaptive immunity, insulin secretion, and sperm capacitation. Moreover, in humans, a higher hHv1 expression/function has been reported in several types of cancer cells. Here we report a multitemplate homology model of the hHv1 channel, built and refined as a dimer in Rosetta. The model was then subjected to extensive Gaussian accelerated molecular dynamics (GaMD) for enhanced conformational sampling, and representative snapshots were extracted by clustering analysis. Combining different structure-and sequence-based methodologies, we predicted a putative ATP-binding site located on the intracellular portion of the channel. Furthermore, GaMD simulations of the ATP-bound dimeric hHv1 model showed that ATP interacts with a cluster of positively charged residues from the cytoplasmic N and C terminal segments. According to the in silico predictions, we found that 3 mM intracellular ATP significantly increases the H + current mediated by the hHv1 channel expressed in HEK293 cells and measured by the patch-clamp technique in an inside-out configuration (2.86 ± 0.63 fold over control at +40 mV). When ATP was added on the extracellular side, it was not able to activate the channel supporting the idea that the ATP-binding site resides in the intracellular face of the hHV1 channel. In a physiological and pathophysiological context, this ATP-mediated modulation could integrate the cell metabolic state with the H + efflux, especially in cells where hHv1 channels are relevant for pH regulation, such as pancreatic β-cells, immune cells, and cancer cells.

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“…The control of the intracellular pH in the β-cells and its proper regulation is essential in the secretory machinery of insulin, which is the pivotal hormone in glucose homeostasis in mammals. It has been shown that Hv1 KO mice possess an impaired metabolism phenotype characterized by hyperglycemia and glucose intolerance due to a reduction in insulin secretion by the beta cells ( Pang et al, 2020 ; Pang et al, 2021 ). PMA stimulation (5 µM) of islet β-cells evoked a secretion of 2.5 ng of insulin per islet, while for the KO hvcn1 β-cells PMA induced a secretion 2.5-fold lower insulin per islet, 1 ng of insulin per islet.…”

Section: Tissue Expression and Physiological Functions Of The Hv1 Cha...mentioning

confidence: 99%

Role of voltage-gated proton channel (Hv1) in cancer biology

et al. 2023

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The acid-base characteristics of tumor cells and the other elements that compose the tumor microenvironment have been topics of scientific interest in oncological research. There is much evidence confirming that pH conditions are maintained by changes in the patterns of expression of certain proton transporters. In the past decade, the voltage-gated proton channel (Hv1) has been added to this list and is increasingly being recognized as a target with onco-therapeutic potential. The Hv1 channel is key to proton extrusion for maintaining a balanced cytosolic pH. This protein-channel is expressed in a myriad of tissues and cell lineages whose functions vary from producing bioluminescence in dinoflagellates to alkalizing spermatozoa cytoplasm for reproduction, and regulating the respiratory burst for immune system response. It is no wonder that in acidic environments such as the tumor microenvironment, an exacerbated expression and function of this channel has been reported. Indeed, multiple studies have revealed a strong relationship between pH balance, cancer development, and the overexpression of the Hv1 channel, being proposed as a marker for malignancy in cancer. In this review, we present data that supports the idea that the Hv1 channel plays a significant role in cancer by maintaining pH conditions that favor the development of malignancy features in solid tumor models. With the antecedents presented in this bibliographic report, we want to strengthen the idea that the Hv1 proton channel is an excellent therapeutic strategy to counter the development of solid tumors.

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Mice lacking the proton channel Hv1 exhibit sex-specific differences in glucose homeostasis

Cited by 5 publications

References 43 publications

Sex-specific effect of P2Y2 purinergic receptor on glucose metabolism during acute inflammation

Sex-specific effect of P2Y2 purinergic receptor on glucose metabolism during acute inflammation

Novel Dimeric hHv1 Model and Structural Bioinformatic Analysis Reveal an ATP-Binding Site Resulting in a Channel Activating Effect

Role of voltage-gated proton channel (Hv1) in cancer biology

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