The Role of Cl Mechanisms


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KCC2 in particular should not affect E Cl . In the anion paradigm, it is argued that KCC2 transports water as well as ions, and functions as an osmotic regulator rather than a chloride regulator (Delpire and Staley, 2014). Neurons have a reduced capacity to regulate cell volume changes when compared to other cell types, probably because they do not have aquaporins (water channels) (Andrew et al., 2007). Because water movement is known to occur with changes in ion concentrations, it has been proposed that CCCs cotransport a fixed ratio of water molecules, sometimes against the osmotic gradient, along with cations and Cl – (MacAulay et al., 2004). This may link GABA A R activation to osmotic regulation in the brain (for review see Cesetti et al. (2011)). Therefore it is possible that changes in chloride homeostasis in neurons are based on water-ion flux, and CCCs do not function to maintain the chloride gradient but rather to determine the osmotic set-point by responding to transmembrane water concentration differences.

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This theory comes with many caveats. Although there is some recent experimental data supporting CCC-mediated water transport (Steffensen et al., 2018), there is no definitive thermodynamic evidence for the theory’s extension to the idea that water itself can cause a gradient that provides the energetic basis of ionic cotransport. Instead, water may be cotransported as a byproduct of normal CCC activity. Finally, even if CCCs are significant water transporters, the natural cell membrane has some permeabilty to water (Hernández and Cristina, 1998) and can also counter osmotic pressures through membrane conformation (stretching or shrinking) and the cytoskeletal elements which act as a ‘sponge’ (Dai et al., 1998; Sachs and Sivaselvan, 2015).

One would need to compare the efficacies of osmotic mechanisms to truly understand what role CCCs might play in volume homeostasis. Furthermore, because they are osmotically active, changes in impermeant anions may also influence cell volume and osmotic homeostasis. Regardless of the mechanism, cellular volume shifts interact with ionic home- ostasis, since increasing volume dilutes concentration. Therefore, my fourth objective was to consider osmolarity and volume constraints in the context of Cl – homeostasis.

Proposition for the central role of impermeant anions in setting the chloride gradient and driving force. (A) In the Glykys et al. (2014) paradigm, [Cl – ] i can vary in different sub-cellular locations secondary to the placement of immobile, impermeant anions. Varying [Cl – ] i in green (left bar) corresponds with the neuron’s dendritic [Cl – ] i differentiation. (B) Taking a closer view at an area in which [Cl – ] i changes in ‘A’, it is proposed that impermeant anions set the [Cl – ] i and therefore the driving force and response to GABAergic activation, while KCC2 transporters may rectify acute currents and regulate water flux, without affecting the stable [Cl – ] i . Top, high [Cl – ] i is caused by local, relatively high extracellular concentrations of impermeant, immobile anions, which repel Cl – so that the local electroneutral balance is maintained. This results in GABAergic shifts to disinhibition (Cl – exits the cell on GABA A R activation). KCC2 does not affect the baseline Cl – concentration. Bottom, low [Cl – ] i is caused by local, relatively high intracellular concentrations of impermeant, immobile anions. This maintains GABAergic inhibition.

Local regulation of Cl

Extending the role of impermeant anions, it has been postulated that impermeant anions are able to mediate local differences in chloride homeostasis because they can act as im- mobile electrostatic components inside or outside a specific area of the cell, influencing the local charges of surrounding ions like Cl – (Glykys et al., 2014). There is some evidence that chloride can be held at different local, sub-cellular levels within domains of a cell (Zhang et al., 2013; Mohapatra et al., 2016), and it is possible that spatial differences in intracellular and extracellular structures could lead to differences in the electric field and hence in the cellular membrane potential, distortions which are invisible during patch-clamping (Savtchenko et al., 2017). Whether this results in distinct local Cl – driving forces — a combination of both V m and E Cl — has implications for the passage of inhibitory signals

Electrodiffusion, the movement of ions through a fluid medium via osmotic and electric forces, is an important determinant of local phenomena. Classically, Rall’s cable equation is a method that incorporates the influence of ionic diffusion on V m in branching neurite structures (Gray and Wu, 1997). However, the Nernst-Planck equation (1.1) is widely considered a more accurate method for calculating ion concentrations and membrane potential in neurites, since it also includes electrical drift: substantial differences in outcomes have been noted when comparing these equations in small structures like dendrites and dendritic spines (Qian and Sejnowski, 1989; Qian and Sejnowski, 1990; Savtchenko et al., 2017).

These variations bring home the importance of understanding the influence of electric forces and charge balance on cellular homeostasis. Whether impermeant anions, which once immobile no longer contribute active energy to the system, can modify local [Cl – ] i and Cl – driving force has caused some debate because of the thermodynamic requirement that creating ‘perpetual ionic motion’ would require an energy source (Kaila et al., 2014). With electrodiffusion considered, it has been argued that the ‘repelling’ action of impermeant anions on Cl – can occur only immediately around an impermeant molecule with high charge density, while the driving force nearby remains unperturbed (Savtchenko et al., 2017). In contrast, differential subcellular expression levels of CCCs use the energy source of the K + gradient to drive activity, and therefore could in theory drive local differences in Cl – that are actively maintained. Because the role of mechanisms of Cl – homeostasis in driving local Cl – driving force dif- ferences is unclear, my next objective was to model electrodiffusion across multiple cellular.

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