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Local impermeant anions establish the neuronal chloride concentration.

ABSTRACT: Neuronal intracellular chloride concentration [Cl(-)](i) is an important determinant of ?-aminobutyric acid type A (GABA(A)) receptor (GABA(A)R)-mediated inhibition and cytoplasmic volume regulation. Equilibrative cation-chloride cotransporters (CCCs) move Cl(-) across the membrane, but accumulating evidence suggests factors other than the bulk concentrations of transported ions determine [Cl(-)](i). Measurement of [Cl(-)](i) in murine brain slice preparations expressing the transgenic fluorophore Clomeleon demonstrated that cytoplasmic impermeant anions ([A](i)) and polyanionic extracellular matrix glycoproteins ([A](o)) constrain the local [Cl(-)]. CCC inhibition had modest effects on [Cl(-)](i) and neuronal volume, but substantial changes were produced by alterations of the balance between [A](i) and [A](o). Therefore, CCCs are important elements of Cl(-) homeostasis, but local impermeant anions determine the homeostatic set point for [Cl(-)], and hence, neuronal volume and the polarity of local GABA(A)R signaling.

SUBMITTER: Glykys J

PROVIDER: S-EPMC4220679 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Local impermeant anions establish the neuronal chloride concentration.

Glykys J J Dzhala V V Egawa K K Balena T T Saponjian Y Y Kuchibhotla K V KV Bacskai B J BJ Kahle K T KT Zeuthen T T Staley K J KJ

Science (New York, N.Y.) 20140201 6171

Neuronal intracellular chloride concentration [Cl(-)](i) is an important determinant of γ-aminobutyric acid type A (GABA(A)) receptor (GABA(A)R)-mediated inhibition and cytoplasmic volume regulation. Equilibrative cation-chloride cotransporters (CCCs) move Cl(-) across the membrane, but accumulating evidence suggests factors other than the bulk concentrations of transported ions determine [Cl(-)](i). Measurement of [Cl(-)](i) in murine brain slice preparations expressing the transgenic fluoropho ...[more]

PMID: 24503855

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Project description:In general, SLC26 solute carriers serve to transport a variety of anions across biological membranes. However, prestin (SLC26a5) has evolved, now serving as a motor protein in outer hair cells (OHCs) of the mammalian inner ear and is required for cochlear amplification, a mechanical feedback mechanism to boost auditory performance. The mechanical activity of the OHC imparted by prestin is driven by voltage and controlled by anions, chiefly intracellular chloride. Current opinion is that chloride anions control the Boltzmann characteristics of the voltage sensor responsible for prestin activity, including Qmax, the total sensor charge moved within the membrane, and Vh, a measure of prestin's operating voltage range. Here, we show that standard narrow-band, high-frequency admittance measures of nonlinear capacitance (NLC), an alternate representation of the sensor's charge-voltage (Q-V) relationship, is inadequate for assessment of Qmax, an estimate of the sum of unitary charges contributed by all voltage sensors within the membrane. Prestin's slow transition rates and chloride-binding kinetics adversely influence these estimates, contributing to the prevalent concept that intracellular chloride level controls the quantity of sensor charge moved. By monitoring charge movement across frequency, using measures of multifrequency admittance, expanded displacement current integration, and OHC electromotility, we find that chloride influences prestin kinetics, thereby controlling charge magnitude at any particular frequency of interrogation. Importantly, however, this chloride dependence vanishes as frequency decreases, with Qmax asymptoting at a level irrespective of the chloride level. These data indicate that prestin activity is significantly low-pass in the frequency domain, with important implications for cochlear amplification. We also note that the occurrence of voltage-dependent charge movements in other SLC26 family members may be hidden by inadequate interrogation timescales, and that revelation of such activity could highlight an evolutionary means for kinetic modifications within the family to address hearing requirements in mammals.

Project description:Disorders of chloride and mixed acid-base disturbances are common in veterinary emergency medicine. Rapid identification of these alterations and the presence of unmeasured anions aid prompt patient assessment and management. This study aimed to determine in dogs and cats if site-specific reference values for [Cl-]:[Na+] ratio and [Na+] - [Cl-] difference accurately identify corrected chloride abnormalities and to evaluate the predictive ability of the [Cl-]:[Na+] ratio for the identification of unmeasured anions. A database containing 33,117 canine, and 7,604 feline blood gas and electrolyte profiles was generated. Institution reference intervals were used to calculate site-specific reference values for the [Cl-]:[Na+] ratio and the [Na+] - [Cl-] difference. Contingency tables were used to assess the ability of these values to correctly identify corrected chloride disorders. Unmeasured anions were estimated by calculating strong ion gap (SIG). Continuous variables were compared using the Mann-Whitney U test. Correlations between continuous variables were assessed using Spearman's rho (rs). In dogs, site-specific reference values for the [Cl-]:[Na+] ratio correctly identified 94.6% of profiles as hyper-, normo-, or hypochloremic. For dogs with normal sodium concentrations, site-specific reference values for the [Na+] - [Cl-] difference correctly identified 97.0% of profiles. In dogs with metabolic acidosis (base deficit > 4.0), [Cl-]:[Na+] ratio and SIG were moderately but significantly negatively correlated (rs -0.592, P < 0.0001). SIG was significantly greater in dogs with metabolic acidosis and hypochloremia compared to those without hypochloremia (P < 0.0001). In cats, site-specific reference values for the [Cl-]:[Na+] ratio correctly identified 93.3% of profiles as hyper-, normo-, or hypochloremic, while site-specific reference values for [Na+] - [Cl-] difference correctly identified 95.1% of profiles. In cats with metabolic acidosis [Cl-]:[Na+] ratio and SIG were moderately significantly negatively correlated (rs -0.730, P < 0.0001). SIG was significantly greater in cats with metabolic acidosis and hypochloremia compared to those without hypochloremia (P < 0.0001). Site-specific values for [Cl-]:[Na+] ratio and [Na+] - [Cl-] difference accurately identify corrected chloride disorders in both dogs and cats and may aid identification of the presence of unmeasured anions.

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Local impermeant anions establish the neuronal chloride concentration.

Publications

Local impermeant anions establish the neuronal chloride concentration.

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