| Title | Authors | Year |
|---|---|---|
| LRRC8A constitutively inhibits pain hypersensitivity in rodent models by restraining NMDA receptor activity at spinal cord synapses | Deng et al. | 2025 |
Overview
LRRC8A, also known as SWELL1, is the pore-forming subunit of the volume-regulated anion channel (VRAC). This complex allows neurons to release chloride and small osmolytes such as taurine and glutamate when the cell swells during excitation. In a healthy neuron, LRRC8A prevents sustained depolarization and protects against the osmotic and electrical imbalance that follows intense synaptic activity. Its loss, therefore, removes a fundamental homeostatic brake on neuronal excitation.
Normal Ionic Regulation
During normal synaptic firing, AMPA receptor activation permits sodium influx and mild depolarization, which in turn unblocks NMDA receptors and allows calcium entry. The combination of sodium and calcium influx increases osmotic pressure inside the cell, pulling in water and slightly swelling the neuron. LRRC8A channels respond to this swelling by opening and releasing chloride, taurine, and other osmolytes to restore equilibrium. This process helps the neuron repolarize and stabilizes the intracellular environment after high-frequency signaling.
The neuron’s steady-state chloride gradient is maintained by two key transporters: KCC2, which exports chloride along with potassium, and NKCC1, which imports chloride along with sodium and potassium. KCC2 keeps intracellular chloride low, making GABAergic currents hyperpolarizing and inhibitory. NKCC1 performs the opposite function and is normally expressed at low levels in mature neurons. Together with LRRC8A, these systems maintain low intracellular chloride concentration and proper inhibitory tone.
Stress-Induced Dysregulation
Chronic stress fundamentally rewires this balance. Cortisol signaling through NR3C1 downregulates KCC2 and LRRC8A while upregulating NKCC1 expression. The result is a net shift toward chloride influx and retention. Neurons gradually accumulate chloride, and the reversal potential for GABA_A receptor channels (E_Cl) shifts toward zero. This means that when GABA opens its chloride channels, the current no longer produces hyperpolarization but can instead depolarize the cell. In this way, stress effectively converts inhibitory input into excitatory drive.
Loss of LRRC8A exacerbates this shift. Without the ability to export chloride and osmolytes through VRACs, intracellular osmotic pressure rises, leading to chronic swelling and sustained depolarization. The neuron becomes easier to activate, and smaller excitatory inputs now trigger full action potentials. This is the ionic foundation of stress sensitization and chronic hyperexcitability.
NMDA Receptor Coupling
The new Science Translational Medicine study demonstrated that LRRC8A directly binds NMDA receptors through its leucine-rich repeat (LRR) domain. Under normal conditions, this interaction restricts NMDA receptor trafficking to the synapse and prevents excessive calcium entry. When LRRC8A is lost, NMDA receptors accumulate at the postsynaptic membrane and remain active longer during signaling. The combination of elevated chloride load and increased NMDA density produces persistent depolarization and excessive calcium influx, the defining features of excitotoxic signaling.
In dorsal horn and dorsal root ganglion neurons, LRRC8A downregulation led to pain hypersensitivity that was reversed by NMDA antagonists. Overexpression of LRRC8A, or intrathecal gene delivery, restored normal NMDA receptor distribution and reversed the pain phenotype. Importantly, human spinal tissue confirmed the presence of LRRC8A–NMDAR complexes, meaning this regulatory mechanism extends beyond rodent models.
Integration into the Stress–Glutamate–ROS Model
In our model, LRRC8A represents the ionic leg of excitotoxic vulnerability. Cortisol upregulates receptor density (via NR3C1) and presynaptic glutamate release, while HSD11B2 and FKBP5 methylation sustain cortisol tone. Meanwhile, LRRC8A loss removes the neuron’s ability to discharge chloride and osmolytes, locking the system in a depolarized, energy-intensive state. The neuron’s mitochondria respond to repeated calcium loading with elevated ROS production. Over time, this overwhelms antioxidant defenses and drives the neurodegenerative process.
Stress therefore operates on three axes:
- Receptor amplification — more NMDA and AMPA receptors, higher conductance.
- Bioenergetic overload — sustained calcium influx and mitochondrial strain.
- Efflux failure — loss of LRRC8A and KCC2 preventing ionic clearance.
These mechanisms converge to convert short-term adaptive excitation into long-term pathological excitation.
Physiological Implications
This chloride polarity shift is the molecular pivot between normal adaptability and chronic excitotoxicity. Stress reduces the number of chloride outflow routes while increasing inflow, making neurons easier to depolarize and maintain in an activated state. The cell’s resting potential drifts closer to threshold, NMDA channels open more easily, and each depolarization carries greater calcium entry and ROS production. Over months or years, this sustained excitatory load causes axonal degeneration and synaptic collapse which is the same trajectory seen in ALS, fibromyalgia, and other stress-related neurodegenerative conditions.
In summary, LRRC8A acts as the “chloride brake” on glutamatergic throughput. When it fails, neurons lose their ability to recover from excitation, becoming trapped in a cycle of depolarization, calcium overload, and oxidative injury. Restoring LRRC8A function or preserving chloride efflux capacity represents a direct therapeutic route to protect the nervous system from the excitatory excess produced by chronic stress.