Regulation of Connexin-Based Channels by Fatty Acids

Abstract

In this mini-review, we briefly summarize the current knowledge about the effects of fatty acids (FAs) on connexin-based channels, as well as discuss the limited information about the impact FAs may have on pannexins (Panxs). FAs regulate diverse cellular functions, some of which are explained by changes in the activity of channels constituted by connexins (Cxs) or Panxs, which are known to play critical roles in maintaining the functional integrity of diverse organs and tissues. Cxs are transmembrane proteins that oligomerize into hexamers to form hemichannels (HCs), which in turn can assemble into dodecamers to form gap junction channels (GJCs). While GJCs communicate the cytoplasm of contacting cells, HCs serve as pathways for the exchange of ions and small molecules between the intra and extracellular milieu. Panxs, as well as Cx HCs, form channels at the plasma membrane that enable the interchange of molecules between the intra and extracellular spaces. Both Cx- and Panx-based channels are controlled by several post-translational modifications. However, the mechanism of action of FAs on these channels has not been described in detail. It has been shown however that FAs frequently decrease GJC-mediated cell-cell communication. The opposite effect also has been described for HC or Panx-dependent intercellular communication, where, the acute FA effect can be reversed upon washout. Additionally, changes in GJCs mediated by FAs have been associated with post-translational modifications (e.g., phosphorylation), and seem to be directly related to chemical properties of FAs (e.g., length of carbon chain and/or degree of saturation), but this possible link remains poorly understood.

Isopimaric acid – a multi‐targeting ion channel modulator reducing excitability and arrhythmicity in a spontaneously beating mouse atrial cell line

“…In summary, the striking similarities in effects between IPA and PUFAs suggest they act via a similar mechanism. Fatty acids are also known to reduce ion currents through connexin-based ion channels, 47 which are widely distributed in the heart. The ion channel-modulating kinship between resin acids and PUFAs suggests the possibility that resin acids can also affect connexin-based ion channels.…”

Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å

“…Furthermore, large-scale gap junctional plaque formation is dependent upon a dense mosaic of protein-lipid interactions. In vitro reconstitution studies have established that plaque assembly and intercellular channel function are dependent on the lipid environment [10][11][12][13][14][15] . However, the molecular basis for these effects remain largely unknown, due to the lack of high-resolution structural information within a lipid bilayer.…”

Mind the Gaps in Tumor Immunity: Impact of Connexin-Mediated Intercellular Connections

“…These different mechanisms of GJIC regulation are at the same time highly responsive to environmental cues, including pro-inflammatory signals. Excellent reviews about regulatory mechanisms of Cx expression and GJIC have been recently published ( 13 – 21 ).…”