Lipid modulation of ion channels through specific binding sites

Abstract

Ion channel conformational changes within the lipid membrane are a key requirement to control ion passage. Thus, it seems reasonable to assume that lipid composition should modulate ion channel function. There is increasing evidence that this implicates not just an indirect consequence of the lipid influence on the physical properties of the membrane, but also specific binding of selected lipids to certain protein domains. The result is that channel function and its consequences on excitability, contractility, intracellular signaling or any other process mediated by such channel proteins, could be subjected to modulation by membrane lipids. From this it follows that development, age, diet or diseases that alter lipid composition should also have an influence on those cellular properties. The wealth of data on the non-annular lipid binding sites in potassium channel from Streptomyces lividans (KcsA) makes this protein a good model to study the modulation of ion channel structure and function by lipids. The fact that this protein is able to assemble into clusters through the same non-annular sites, resulting in large changes in channel activity, makes these sites even more interesting as a potential target to develop lead compounds able to disrupt such interactions and hopefully, to modulate ion channel function. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

Activation of Calcium- and Voltage-gated Potassium Channels of Large Conductance by Leukotriene B4

“…In this work, we demonstrated that this site can also accommodate LTB4. Therefore, two endogenous lipids from different chemical groups (heterocyclic cholane steroids and linear leukotrienes) can share their site of action on an ion channel protein, an unusual phenomenon because lipid-sensing sites on ion channels, BK in particular, do not share ligands from different lipid species (1,43). The physiological implications of such overlap remain to be explored.…”

“…Regulation of ion channel function, of BK in particular, due to direct interaction between ion channel protein and physiologically relevant endogenous lipids represents a growing area of research (1,31). Indeed, several recent studies have shown direct modulation of BK channel function by fatty acids (10,32), phosphatidylinositol 4,5-bisphosphate and other phosphoinositides (8), membrane phosphoglycerides (33), and physiologically relevant steroids, including cholesterol (7,34), stress (35) and sex hormones (9), and bile acids and related cholane steroids (12,28).…”

“…Regulation of cell physiology by direct targeting of cell membrane ion channel proteins by lipid signaling molecules represents an area of expanding investigation (1). In particular, lipid regulation of Ca 2ϩ -and voltage-gated potassium channels of large conductance (BK) 3 has received increasing attention because these channels control numerous physiological processes, such as smooth muscle tone, neuronal firing, hormonal release, immune responses, and cancer cell growth (2)(3)(4).…”

Dynamic analysis of phospholipid metabolism of mouse macrophages treated with common non-steroidal anti-inflammatory drugs

“…Also, PAs have a strong affinity to calcium ion channels, PA binding to calcium ion channels can induce an outflow of intracellular Ca 2? [4]. We suppose that NSAIDs have certain effects on PAs when intervening in the inflammatory cell model.…”

“…PA substances can inhibit the release of intracellular Ca 2? , thereby reducing the endoplasmic reticulum stress caused by calcium and affecting macrophage endocytosis [4]. Moreover, PA substances can activate protein kinase C and other related pathways, thus affecting the cell cycle arrest and apoptosis [5].…”