Chloride
Chloride is the most abundant extracellular anion and the primary counterion to Na⁺ in the ECF. Unlike most trace elements, it acts purely ionically — as the permeant anion of the GABA-A receptor (neuronal inhibition), the substrate of CFTR (airway/intestinal fluid secretion), the product of parietal cell HCl synthesis (gastric acid), and the exchange partner in the AE1 chloride shift (CO₂ transport in erythrocytes). Its renal handling by NKCC2 and NCC is the molecular target of two of the most widely used diuretic classes.
Overview & Atomic Properties
| Property | Value |
|---|---|
| Atomic number (Z) | 17 |
| Atomic mass | 35.45 u (³⁵Cl 75.8%, ³⁷Cl 24.2%) |
| Electron configuration | [Ne] 3s² 3p⁵ |
| Ionic radius (Cl⁻) | 181 pm |
| Electronegativity (Pauling) | 3.16 |
| Plasma [Cl⁻] | 103 mEq/L (paired with Na⁺ ~142 mEq/L + HCO₃⁻ ~24 mEq/L) |
| Intracellular [Cl⁻] (neurons) | 4–10 mEq/L (maintained low by KCC2); ~25–40 mEq/L in neonates (NKCC1-dominant) |
| Gastric lumen | ~150 mEq/L (secreted as HCl by parietal cells) |
| Sweat [Cl⁻] | 10–40 mEq/L (normal); >60 mEq/L (cystic fibrosis) |
| Dietary sources | Table salt (NaCl), processed foods, seaweed, olives, soy sauce |
Biological Roles
1. GABA-A Receptor — Neuronal Inhibition
GABA released by inhibitory interneuron into synapse
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GABA binds α–β interface of GABA-A receptor (pentameric Cys-loop channel)
Channel pore opens (~1–3 ms open time per burst)
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Cl⁻ influx (ECF 103 mEq/L → ICF ~4 mEq/L) down electrochemical gradient
E_Cl ≈ −70 to −75 mV (in mature neurons where KCC2 maintains low [Cl⁻]i)
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Membrane hyperpolarises toward E_Cl → INHIBITION
Shunting inhibition: increased conductance resists depolarisation by EPSPs
Allosteric modulators at GABA-A:
Benzodiazepines → ↑ frequency of Cl⁻ channel opening (require GABA)
Barbiturates → ↑ duration of Cl⁻ channel opening; direct gate at high dose
Neurosteroids → potentiate + directly activate (δ subunit)
Propofol → potentiate + direct activation
NEONATAL POLARITY: NKCC1 high / KCC2 low → [Cl⁻]i ~30 mEq/L
E_Cl ≈ −40 mV (depolarised relative to Vm ~−70 mV)
→ GABA-A opening causes Cl⁻ EFFLUX → DEPOLARISATION → EXCITATORY
→ "GABA switch" to inhibition occurs as KCC2 is upregulated postnatally
2. CFTR — Epithelial Fluid Secretion
CFTR (ABCC7) is a cAMP-regulated Cl⁻ channel at the apical surface of secretory epithelia (airways, pancreatic ducts, intestinal crypts, sweat gland ducts). Activation: adenylyl cyclase → cAMP → PKA → phosphorylates R-domain → channel opens (ATP binds NBD1/NBD2). In airways, Cl⁻ export draws water into the airway surface liquid (ASL), maintaining mucociliary clearance. In sweat glands, CFTR reabsorbs Cl⁻ from the primary sweat, keeping sweat hypotonic.
3. Chloride Shift (Hamburger Phenomenon)
In systemic capillaries: CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻ (catalysed by carbonic anhydrase II in RBCs). HCO₃⁻ exits via AE1/Band 3 (SLC4A1) in exchange for extracellular Cl⁻ → Cl⁻ influx maintains electroneutrality → plasma CO₂ transported as HCO₃⁻ (~70% of total CO₂ transport). Reversed at the lung: Cl⁻ exits → HCO₃⁻ re-enters → CA reforms CO₂ for exhalation.
4. Gastric HCl Secretion
Parietal cells combine two transporters: H⁺/K⁺-ATPase (apical canaliculus, secretes H⁺) + SLC26A7 (Cl⁻/HCO₃⁻ exchanger, exports Cl⁻ into lumen). H⁺ + Cl⁻ → HCl (pH 1.5–3.5 in gastric lumen). Proton pump inhibitors (omeprazole) irreversibly block H⁺/K⁺-ATPase; H₂ blockers (ranitidine) reduce cAMP-driven parietal cell stimulation.
Absorption & Renal Handling
| Nephron segment | Fraction reabsorbed | Mechanism | Diuretic target |
|---|---|---|---|
| Proximal convoluted tubule | ~65% | Paracellular (lumen-positive late PCT) + NHE3-coupled indirectly | — |
| Thick ascending limb (TALH) | ~25% | NKCC2 (SLC12A1): Na⁺+K⁺+2Cl⁻ cotransport | Loop diuretics (furosemide, bumetanide) |
| Distal convoluted tubule | ~5% | NCC (SLC12A3): Na⁺+Cl⁻ cotransport | Thiazides (hydrochlorothiazide, chlorthalidone) |
| Collecting duct | ~3–4% | AE1/pendrin in intercalated cells (paracellular) | — |
Deficiency & Toxicity
| Condition | Mechanism | Features / Treatment |
|---|---|---|
| Cystic fibrosis (CF) | CFTR mutations → absent/dysfunctional Cl⁻ channel → dehydrated viscous ASL → mucus plugging → chronic Pseudomonas infection → bronchiectasis; pancreatic insufficiency; CBAVD | ΔF508 most common (>70% alleles); Trikafta (elexacaftor/tezacaftor/ivacaftor) corrector+potentiator triple therapy improves FEV₁ by ~14% and dramatically improves QoL in >90% of CF patients |
| Bartter syndrome | NKCC2 (Type I), ROMK (Type II), or CLCNKB (Type III) mutations → impaired TALH Cl⁻ reabsorption → salt wasting + hypokalaemia + metabolic alkalosis | Polyhydramnios, neonatal salt wasting, secondary hyperaldosteronism; treat with NSAIDs + K⁺ supplementation |
| Gitelman syndrome | NCC (SLC12A3) mutation → DCT Cl⁻ reabsorption defect → hypokalaemia + hypomagnesaemia + metabolic alkalosis + hypocalciuria | Milder than Bartter, presents in adults; treat with Mg²⁺ + K⁺ supplementation |
| Hyperchloraemic metabolic acidosis | HCO₃⁻ loss (diarrhoea) or Cl⁻ gain (large volume normal saline, 154 mEq/L Cl⁻) → non-anion gap acidosis | Normal AG; distinguish from anion-gap acidosis (ketones, lactate, uraemia) |
Connections
References
- Csanady L, Vergani P, Gadsby DC. Structure, gating, and regulation of the CFTR anion channel. Physiol Rev. 2019;99(1):707-738. doi:10.1152/physrev.00007.2018 · PubMed 30516487
- Ben-Ari Y. Excitatory actions of GABA during development. Nat Rev Neurosci. 2002;3(9):728-39. doi:10.1038/nrn920 · PubMed 12209121
- Hall JE, Hall ME. Guyton and Hall Textbook of Medical Physiology. 14th ed. Elsevier; 2021.
- Berg JM, Tymoczko JL, Stryer L. Biochemistry. 9th ed. W.H. Freeman; 2019.