BK channel overexpression on plasma membrane of fibroblasts from Hutchinson-Gilford progeria syndrome

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder wherein symptoms resembling aspects of aging are manifested at a very early age. It is a genetic condition that occurs due to a de novo mutation in the LMNA gene encoding for the nuclear structural protein lamin A. The lamin family of proteins are thought to be involved in nuclear stability, chromatin structure and gene expression and this leads to heavy effects on the regulation and functionality of the cell machinery. The functional role of the large-conductance calcium-activated potassium channels (BKCa) is still unclear, but has been recently described a strong relationship with their membrane expression, progerin nuclear levels and the ageing process. In this study, we found that: i) the outward potassium membrane current amplitude and the fluorescence intensity of the BKCa channel probe showed higher values in human dermal fibroblast obtained from patients affected by HGPS if compared to that from healthy young subjects; ii) this result appears to correlate with a basic cellular activity such as the replicative boost. We suggest that studying the HGPS also from the electrophysiological point of view might reveal new clues about the normal process of aging.

The Role of KCNMB1 and BK Channels in Myofibroblast Differentiation and Pulmonary Fibrosis

“…BK channels have recently been shown to couple with mechanotransduction signals to promote osteoblast activation (23). BK channels also promote the migration and proliferation of synoviocytes (24), and the proliferation of dermal fibroblasts (25). The function of BK channels in lung fibroblasts, and particularly their ability to modulate myofibroblast differentiation, has not been described.…”

Calcium-activated big conductance (BK) potassium channels traffic through nuclear envelopes into kinocilia in skate electrosensory cells

“…Hutchinson-Gilford progeria syndrome (HGPS) manifests as premature aging and is caused by genetic mutations in lamin A that leads to progressive breakdown of the nuclear envelope [38]. Zironi et al demonstrated BK channel overexpression in plasma membranes by electrophysiology and immunofluorescence of dermal fibroblasts isolated from HGPS patients compared to young and elderly control donors [39]. These results are consistent with a model where functional BK channels that normally partition between plasma membranes and nuclear envelopes become overexpressed in plasma membranes when nuclear envelopes are genetically disrupted.…”

Epigenomic signature of the progeroid Cockayne syndrome exposes distinct and common features with physiological ageing

“…Alzheimer’s and Parkinson’s disease) 54 , and they may play a role in neurodegeneration in CS. Interestingly, remodelling of K + channels in dermal fibroblasts has been associated with the successful ageing of centenarians 52 , while overexpression of K + channels has been observed in HGPS cells 55 . Several genes coding for ion channels identified as differentially methylated in our study such as GABA ( GABRD, GABRB3 ), glutamate ( GRIN1, 2D ) or acetylcholine receptors ( CHRNA2, B2 ), are of particular interest since they are also main neurotransmitter receptors that regulate brain function. Genes for active transmembrane transporters mainly involve the solute carrier group of transport proteins (SLCs) that carry a wide variety of substrates including ions, nutrients, and/or neurotransmitters through plasma/organelle membrane, including in fibroblasts 56 .…”