Calcium signalling; calcium channels

Hutan · May 1, 2023

Split thread
from Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain, Md Shafiqur Rahman, et al, 2020
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I was reading about calcium channels the other day.
This reference about them is very readable and interesting. Don't be put off by the reference to breast cancer, there's a lot of general stuff.
Calcium signaling: breast cancer’s approach to manipulation of cellular circuitry

Calcium signalling paper said:

When calcium ions (Ca2+) flow into a cell, they can bind to calcium-binding proteins to ultimately initiate cell functions. Paradoxically, however, this versatile single element universally participates in almost every single cell process: death (Boehning et al. 2003; Orrenius et al. 2003), cell cycle (Colomer et al. 1994; Kahl and Means 2004), division (Rasmussen and Means 1989), migration (Brundage et al. 1991; Giannone et al. 2004; Hahn et al. 1992; Yang and Huang 2005), invasion (Kato et al. 2007; Sun et al. 2014), metabolism (Cardenas et al. 2010), differentiation (Carey and Matsumoto 1999; Hennings et al. 1980; Holliday et al. 1991), autophagy (Cardenas et al. 2010; Medina et al. 2015), and transcription (Dolmetsch et al. 1998, 2001), as well as participating in many specialized cell functions: angiogenesis (Dragoni et al. 2011), fertilization (Miao et al. 2012; Saunders et al. 2002; Steinhardt et al. 1977), insulin secretion (Grodsky and Bennett 1966; Prentki and Wollheim 1984), synaptic transmission (Brose et al. 1992; Fernandez-Chacon et al. 2001), muscle contraction (Gergely et al. 1993; Sorenson et al. 1995), and immune response (Bhakta et al. 2005).
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Calcium signalling paper said:

This is perhaps why scientists quote the Nobel prize winning Otto Loewi’s proclamation, “Ja Kalzium, das ist alles” (Carafoli 2002), which literally translates to “Yes calcium, that’s all,” but instead is often interpreted as “calcium is everything” or “calcium is universal” (Brini and Carafoli 2000; Kaestner 2013).
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Given the wide varieties of processes calcium is involved with, it would almost be surprising for it not to be involved in chronic pain and in ME/CFS.

The paper I linked has a nice diagram of a whole lot of different calcium pumps, including ATP driven ones (which is what the ATP2C1 one seems to be).

What I thought was really interesting, aside from the number of different types of calcium channels, is that the signalling is a lot more complicated than just the concentration of calcium inside the cell. There are things like pulses of calcium inflow, with the speed of the pulse affecting the signalling. And then there is the gradient of calcium within the cell, and all sorts of other details that makes things work.

It's amazing stuff.

Calcium signalling paper said:

However, the complex versatility of calcium ions in the wide variety of cell functions, as outlined above, is not possible in a binary world. Otherwise, increases in cytosolic calcium would simultaneously trigger all cell functions. Rather, the versatility of calcium ions is possible on a spectrum of calcium signals, which is the topic of the next section. Calcium signals can be big or small, be fast or long lasting, and be global or local. These amplitude, frequency, and spatial spectra ultimately regulate the discrimination between different cell functions and give the cell the tools to appropriately “choose” its fate.
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Ravn · May 2, 2021

Hutan said: ↑

Given the wide varieties of processes calcium is involved with, it would almost be surprising for it not to be involved in chronic pain and in ME/CFS.
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This recent hypothesis paper proposes a calcium problem in ME (not that I understand any of it).

Major players involved are the sodium–potassium ATPase (Na+/K+-ATPase), the sodium-proton-exchanger (NHE1; SLC9A1) and the sodium-calcium-exchanger (NCX) (Fig. 2). The isoform in skeletal muscle is NCX3 (SLC8A3) [37]. The NCX can reverse its transport direction to import calcium instead of exporting it under conditions of a strong rise in intracellular sodium. In the following we try to work out how sodium overload could occur in ME/CFS which would then entail calcium overload as the final damaging mechanism.
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https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02833-2

Discussed here: https://www.s4me.info/threads/patho...ces-in-me-cfs-2021-wirth-scheibenbogen.20256/

Sly Saint · Dec 3, 2023

Loss of mitochondrial Ca2+ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity
Abstract
Mitochondrial calcium concentration ([Ca2+]m) plays an essential role in bioenergetics, and loss of [Ca2+]m homeostasis can trigger diseases and cell death in numerous cell types. Ca2+ uptake into mitochondria occurs via the mitochondrial Ca2+ uniporter (MCU), which is regulated by three mitochondrial Ca2+ uptake (MICU) proteins localized in the intermembrane space, MICU1, 2, and 3. We generated a mouse model of systemic MICU3 ablation and examined its physiological role in skeletal muscle. We found that loss of MICU3 led to impaired exercise capacity. When the muscles were directly stimulated there was a decrease in time to fatigue. MICU3 ablation significantly increased the maximal force of the KO muscle and altered fibre type composition with an increase in the ratio of type IIb (low oxidative capacity) to type IIa (high oxidative capacity) fibres. Furthermore, MICU3-KO mitochondria have reduced uptake of Ca2+ and increased phosphorylation of pyruvate dehydrogenase, indicating that KO animals contain less Ca2+ in their mitochondria. Skeletal muscle from MICU3-KO mice exhibited lower net oxidation of NADH during electrically stimulated muscle contraction compared with wild-type. These data demonstrate that MICU3 plays a role in skeletal muscle physiology by setting the proper threshold for mitochondrial Ca2+ uptake, which is important for matching energy demand and supply in muscle.

Key points

Mitochondrial calcium uptake is an important regulator of bioenergetics and cell death and is regulated by the mitochondrial calcium uniporter (MCU) and three calcium sensitive regulatory proteins (MICU1, 2 and 3).

Loss of MICU3 leads to impaired exercise capacity and decreased time to skeletal muscle fatigue.

Skeletal muscle from MICU3-KO mice exhibits a net oxidation of NADH during electrically stimulated muscle contractions, suggesting that MICU3 plays a role in skeletal muscle physiology by matching energy demand and supply.

https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP284894

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Calcium signalling; calcium channels

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