Figure 4.

Two models are described to account for how NKCC1 function leads to multiorgan failure. (A) Each organ sends afferent fibers to the spinal cord to modulate autonomic function. These neurons have their cell bodies in dorsal root ganglia. Parallel arrows indicate spinal cord ascending and descending pathways. (B) All major organs have smooth muscle cells where NKCC1 accumulates Cl⁻ above thermodynamic potential equilibrium. Opening of Cl⁻ channels depolarizes the membrane triggering the opening of voltage-sensitive Ca²⁺ channels, Ca²⁺ entry, and contraction. NKCC1 dysfunction leads to collapse of Cl⁻ gradients in both sensory (DRG) neurons and smooth muscle cells, thereby contributing to the multiorgan pathology.