Biology subjects

Benson, C. J.

Publications and source records attributed to Benson, C. J..

4 recordsLinked to original sources

bioRxiv2026

A Quartet of Native Orai Channel Isoforms Orchestrates Graded NFAT Activation and Transcription

The Ca{superscript 2} release-activated Ca{superscript 2} (CRAC) channel mediates store-operated calcium entry (SOCE), a ubiquitous pathway essential for many cell types, including immune cells. Three Orai (Orai1/2/3) proteins constitute the plasma membrane pore-forming units of CRAC channels that are activated by the endoplasmic reticulum (ER) Ca2+-sensing STIM1/2 proteins when ER Ca2+ stores are depleted. Orai1/2/3 are differentially expressed across primary cells with discernible differences in their structures and biophysical properties. Further, Orai1 has two alternatively translated isoforms: long mammalian-specific Orai1 and the 63-residue shorter Orai1{beta}, which is evolutionarily older and conserved across vertebrates. Whether Orai1/1{beta}/2/3 produce unique cytosolic Ca{superscript 2} signatures that bias transcriptional responses through effectors like NFAT is unclear. Here, we used HEK293 cells engineered to express one native Orai isoform and show that all Orai isoforms couple to NFAT1/4 induction. The magnitude of NFAT1/4 induction for each Orai isoform matches that of SOCE, with the following profile: Orai1{beta}>Orai1>>Orai2>Orai3. Near-native re-expression of either Orai1 or Orai1{beta} in primary murine Orai1-/- CD4 T cells restored SOCE, NFAT activation, cytokine production and promoted near identical transcriptional responses enriched for immune activation pathways. An analysis of genetic and clinical data of human individuals showed that homozygous null mutations selectively abolishing Orai1 are not associated with disease resembling CRAC channelopathy. Primary T cells from individuals homozygous or heterozygous for an Orai1 null mutation showed enhanced, rather than impaired, SOCE and NFAT induction. Our data indicate that NFAT activation and transcriptional outputs are primarily driven by the graded strength of SOCE mediated by each isoform of the Orai quartet.

cell biology↗

bioRxiv2025

TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance

Inter-organelle signaling mechanisms, particularly those at the lysosomes-mitochondria interface, are critical for cancer cell metabolism, mitophagy and survival. However, the incomplete understanding of these mechanisms has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we demonstrate the lysosomal Ca{superscript 2}-release channel TRPML1 as a master regulator of mitochondrial bioenergetics in TNBC cells. TRPML1 knockdown (ML1-KD) in TNBC cells selectively compromises mitochondrial respiration, reprograms cell metabolism, and induces mitochondrial fragmentation without impacting non-cancerous cells. Mitochondria of ML1-KD TNBC cells sequester around the endoplasmic reticulum (ER), increasing mitochondria-ER contact sites at the expense of mitochondria-lysosomes contacts. Mechanistically, ML1-KD reduces lysosomal acidification, thus hindering autophagic flux and completion of autophagy. ML1-KD inhibits TFEB-mediated mitophagy and oxidative defense mechanisms while causing mitochondrial Ca2+ overload, further impairing mitochondrial function. These alterations render ML1-KD TNBC cells highly sensitive to doxorubicin and paclitaxel at low doses that are typically ineffective on their own. Together, our findings establish TRPML1 as a critical inter-organelle regulator and highlight its potential as a therapeutic target to exploit the metabolic vulnerabilities of TNBC cells.

cancer biology↗

bioRxiv2025

Genetic Deletion of ASIC3 Alters Left Ventricular Remodeling and Autonomic Function After Myocardial Infarction in Mice

Chronic overactivation of neurohormonal systems is the principal driver of adverse cardiac remodeling following myocardial infarction (MI). Recent data suggest that ablating cardiac afferent neurons in rats attenuates left ventricular (LV) remodeling following MI by blocking this overactivation. Our lab has shown that acid-sensing ion channels (ASICs) are highly expressed in cardiac afferents and may sense myocardial acidosis. We hypothesized that genetic deletion of ASICs might abrogate disadvantageous remodeling after MI by disrupting afferent signaling pathways otherwise resulting in overactivation of neurohormonal responses. To test this hypothesis, we induced MI by coronary artery ligation in wild type (WT) and ASIC3-/- mice and assessed cardiac remodeling by serial echocardiography. We found that ASIC3-/- mice had less LV dilation relative to MI size, increased LV mass, and increased stroke volume compared to WT mice after MI. To investigate a potential role of the autonomic nervous system, we measured renal and splanchnic sympathetic nerve activity, heart rate and systolic blood pressure variability (sBPV), and hemodynamic responses to atropine and propranolol. In addition, we assessed baroreceptor-heart rate and baroreceptor-renal sympathetic nerve activity (RSNA) reflex function. Following MI, ASIC3-/- mice had lower baroreceptor-RSNA reflex sensitivity than WT mice, associated with elevated sBPV. Importantly, sBPV correlated significantly with post-MI changes in LV mass in ASIC3-/- but not WT mice. Our data shows that ASIC3 plays an important role in cardiac remodeling after MI potentially via modulation of baroreflex sensitivity and sBPV. ASIC3 may be further investigated as a potential therapeutic target in heart failure.

physiology↗

bioRxiv2023

Acid enhances salt taste by activating the epithelial sodium channel

Salt is often used to enhance the flavor of foods and drinks, and in turn, some foods and drinks may intensify the taste of salt. For example, highly acidic carbonated beverages sometimes accompany salty snacks, and margaritas made with acidic citrus are served in salt-rimmed glasses. However, whether and how acid might enhance salt taste remain unknown. Epithelial sodium channels (ENaC) in tongue taste cells detect dietary sodium. We found that acid irreversibly increased ENaC channel activity, with half-maximal activation occurring at pH 2.6. Acid altered ENaC gating by increasing the rate of channel opening and reducing the rate of channel closing. Acidic beverages Coca-Cola(R) and Pepsi(R) (pH 2.2-2.4) also stimulated ENaC current but Diet Coke(R) (pH 3.2) did not. In humans, we found that acid reduced the sodium taste detection threshold. These findings identify a functional interplay between dietary sodium and acid--by modulating ENaC gating, acid enhances salt taste.

physiology↗