Abstract
The calcium/calmodulin-gated KCa3.1 channel regulates normal and abnormal mitogenesis by controlling K+-efflux, cell volume, and membrane hyperpolarization-driven calcium-entry. Recent studies suggest modulation of KCa3.1 by omega-3 fatty acids as negative modulators and impaired KCa3.1 functions in the inherited lysosomal storage disorder (LSD), Fabry disease (FD). In the first part of present study, we characterize KCa3.1 in murine and human fibroblasts and test the impact of omega-3 fatty acids on fibroblast proliferation. In the second, we study whether KCa3.1 is altered in the LSDs, FD, and Niemann-Pick disease type C (NPC). Our patch-clamp and mRNA-expression studies on murine and human fibroblasts show functional expression of KCa3.1. KCa currents display the typical pharmacological fingerprint of KCa3.1: Ca2+-activation, potentiation by the positive-gating modulators, SKA-31 and SKA-121, and inhibition by TRAM-34, Senicapoc (ICA-17043), and the negative-gating modulator, 13b. Considering modulation by omega-3 fatty acids we found that α-linolenic acid (α-LA) and docosahexanenoic acid (DHA) inhibit KCa3.1 currents and strongly reduce fibroblast growth. The α-LA-rich linseed oil and γ-LA-rich borage oil at 0.5% produce channel inhibition while α-LA/γ-LA-low oils has no anti-proliferative effect. Concerning KCa3.1 in LSD, mRNA expression studies, and patch-clamp on primary fibroblasts from FD and NPC patients reveal lower KCa3.1-gene expression and membrane expression than in control fibroblasts. In conclusion, the omega-3 fatty acid, α-LA, and α-LA/γ-LA-rich plant oils, inhibit fibroblast KCa3.1 channels and mitogenesis. Reduced fibroblast KCa3.1 functions are a feature and possible biomarker of cell dysfunction in FD and NPC and supports the concept that biased lipid metabolism is capable of negatively modulating KCa3.1 expression.
Highlights
The intermediate-conductance calcium/calmodulin-gated potassium channel KCa3.1 is expressed in a variety of tissues such red and white blood cell lineage, epithelia, and endothelia (Wei et al, 2005)
We found that murine and human dermal fibroblasts express amounts of functional KCa3.1 channels
KCa3.1 channel functions have been linked to abnormal cell proliferation, pathological tissue remodeling and fibrosis of a variety of organs, chronic inflammation, and autoimmune diseases (Wulff and Zhorov, 2008; Roach et al, 2013; Wulff and Köhler, 2013; Feske et al, 2015; Huang et al, 2015; Köhler et al, 2016)
Summary
The intermediate-conductance calcium/calmodulin-gated potassium channel KCa3.1 (encoded by the KCNN4 gene) is expressed in a variety of tissues such red and white blood cell lineage, epithelia, and endothelia (Wei et al, 2005). The endogenous omega-6 fatty, arachidonic acid (AA) and AA-metabolites such as some 11,12 epoxyeicosatrienoic acid and 20-hydroxyeicosatetraenoic acid (20-HETE), have been found to inhibit cloned human KCa3.1 that required mechanistically the inner pore lining amino acid residues, T250 and V275 as putative interaction sites (Hamilton et al, 2003; Kacik et al, 2014). The cell biological meaning of this modulation of KCa3.1 by omega-3/6 fatty acid is unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
