The L-type voltage-gated Ca2+ channel CaV1.2 regulates fibroblast-like synoviocytes invasiveness during rheumatoid arthritis
- 1Baylor College of Medicine
Abstract
Fibroblast-like synoviocytes (FLS) are major drivers of synovial tissue inflammation and damage during rheumatoid arthritis (RA). A hallmark of the aggressiveness of RA-FLS is their invasiveness but the molecular mechanisms that regulate this invasiveness remain poorly understood. The KCa1.1 (BK, Slo1, MaxiK, KCNMA1 ) potassium channel is a major regulator of RA-FLS pathogenicity and inhibiting KCa1.1 expression or its activity with selective blockers reduces RA-FLS invasiveness and reduces disease severity and joint damage in rat models of RA. KCa1.1 blockade induces a Ca 2+ influx in RA-FLS whose intracellular signaling results in increased cell adhesion to the extracellular matrix and thus a reduction in cell migration. However, the identity of the Ca 2+ -permeable channel responsible for the Ca 2+ influx has remained elusive. Here, we demonstrate the co-expression of KCa1.1 with the L-type voltage-gated CaV1.2 channels at the plasma membrane of primary human and rat FLS. Selective blocking of the CaV1.2 channel blunts the Ca 2+ influx induced by KCa1.1 blockade and abrogates the effects of KCa1.1 blockade on RA-FLS invasiveness, migration, cell shape, and podoplanin expression. Whereas KCa1.1 blockers reduce disease severity in rat models of RA, treating rats with the collagen-induced arthritis model of RA with both blockers of KCa1.1 and CaV1.2 eliminates the therapeutic benefits of treatment with KCa1.1 blockers alone. Together, these data demonstrate a physical and functional coupling of KCa1.1 and CaV1.2 channels in FLS during RA and its rat model that regulate the invasive phenotype of the FLS through modulation of intracellular Ca 2+ homeostasis. Significance Statement This study identifies the expression of CaV1.2 Ca 2+ channels in primary fibroblast-like synoviocytes isolated from the joints of patients with rheumatoid arthritis. CaV1.2 channels are functionally coupled with KCa1.1 K + channels to regulate the highly invasive phenotype of these synoviocytes, as blocking KCa1.1 induces a Ca 2+ influx through opening of CaV1.2 that increases the adhesion of fibroblast-like synoviocytes and inhibits their migration. Conversely, blocking CaV1.2 negates the beneficial effects of KCa1.1 on the synoviocytes in vitro and abrogates the therapeutics effects of a KCa1.1 blocker in reducing clinical signs of collagen-induced arthritis.
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BibTeX
@misc{tanner2026ltype,
title = {{The L-type voltage-gated Ca2+ channel CaV1.2 regulates fibroblast-like synoviocytes invasiveness during rheumatoid arthritis}},
author = {M. R. Tanner and R. N. Elston and M. J. Brandt and B. A. Morse and L. Sun and S. Zou and J. M. Hyser and F. T. Horrigan and T. Laragione and P. S. Gulko and C. Beeton},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.758622},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.758622v1},
note = {Public domain},
}
RIS
TY - UNPB
TI - The L-type voltage-gated Ca2+ channel CaV1.2 regulates fibroblast-like synoviocytes invasiveness during rheumatoid arthritis
AU - M. R. Tanner
AU - R. N. Elston
AU - M. J. Brandt
AU - B. A. Morse
AU - L. Sun
AU - S. Zou
AU - J. M. Hyser
AU - F. T. Horrigan
AU - T. Laragione
AU - P. S. Gulko
AU - C. Beeton
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.758622
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.758622v1
AB - Fibroblast-like synoviocytes (FLS) are major drivers of synovial tissue inflammation and damage during rheumatoid arthritis (RA). A hallmark of the aggressiveness of RA-FLS is their invasiveness but the molecular mechanisms that regulate this invasiveness remain poorly understood. The KCa1.1 (BK, Slo1, MaxiK, KCNMA1 ) potassium channel is a major regulator of RA-FLS pathogenicity and inhibiting KCa1.1 expression or its activity with selective blockers reduces RA-FLS invasiveness and reduces disease severity and joint damage in rat models of RA. KCa1.1 blockade induces a Ca 2+ influx in RA-FLS whose intracellular signaling results in increased cell adhesion to the extracellular matrix and thus a reduction in cell migration. However, the identity of the Ca 2+ -permeable channel responsible for the Ca 2+ influx has remained elusive. Here, we demonstrate the co-expression of KCa1.1 with the L-type voltage-gated CaV1.2 channels at the plasma membrane of primary human and rat FLS. Selective blocking of the CaV1.2 channel blunts the Ca 2+ influx induced by KCa1.1 blockade and abrogates the effects of KCa1.1 blockade on RA-FLS invasiveness, migration, cell shape, and podoplanin expression. Whereas KCa1.1 blockers reduce disease severity in rat models of RA, treating rats with the collagen-induced arthritis model of RA with both blockers of KCa1.1 and CaV1.2 eliminates the therapeutic benefits of treatment with KCa1.1 blockers alone. Together, these data demonstrate a physical and functional coupling of KCa1.1 and CaV1.2 channels in FLS during RA and its rat model that regulate the invasive phenotype of the FLS through modulation of intracellular Ca 2+ homeostasis. Significance Statement This study identifies the expression of CaV1.2 Ca 2+ channels in primary fibroblast-like synoviocytes isolated from the joints of patients with rheumatoid arthritis. CaV1.2 channels are functionally coupled with KCa1.1 K + channels to regulate the highly invasive phenotype of these synoviocytes, as blocking KCa1.1 induces a Ca 2+ influx through opening of CaV1.2 that increases the adhesion of fibroblast-like synoviocytes and inhibits their migration. Conversely, blocking CaV1.2 negates the beneficial effects of KCa1.1 on the synoviocytes in vitro and abrogates the therapeutics effects of a KCa1.1 blocker in reducing clinical signs of collagen-induced arthritis.
ER -