Chloride Regulation in the Pain Pathway

Signaling events that may increase NKCC-mediated Cl− influx include phosphorylation (star 1), protein trafficking (star 2) or decreases in intracellular Na+ (star 3). Star 1: In contrast to KCC2, phosphorylation of NKCC1 results in an increase in activity, CaMKIIα (downstream of mGluR1/5), PKCδ and ERK have all been shown to increase NKCC1 activity, although it is not known if these kinases directly phosphorylate NKCC1. JNK also increases NKCC1 activity via direct phosphorylation of the co-transporter. A separate family of kinases, which are regulated by tonicity and cellular stress, positively modulate NKCC1. WNK1/4 act via SPAK and/or OSR1 to phosphorylate NKCC1. WNK3 also increases Cl− accumulation via NKCC1 and decreases KCC2 activity, which augments the net effect of NKCC1 stimulation in neurons that express both co-transporters. It is not known if WNK3 directly phosphorylates NKCC1 (and KCC2) or if it acts through SPAK/OSR1. SPAK and OSR1 interact with the N-terminus of NKCC1, where the co-transporter is phosphorylated, making these kinases ideal candidates as integrators of signaling that converges on NKCC1. Star 2: Dynamic regulation of the density of NKCC in the cell membrane may also influence rates of Cl− influx. An increase in intracellular cAMP concentration increases membrane delivery of NKCC2 in a Vamp2/3-dependent fashion. It is not known if this mechanism is also active at NKCC1. Star 3: A drop in the concentration of intracellular Na+ secondary to an increase in Na+/K+-ATPase may result in an increase in NKCC1 activity. This sequence of events may follow the increase in Na+ that occurs in association with an intense burst of neuronal activity. Star A, B and C: Persistent nociceptor activation caused by an intracolonic irritant injection causes an increase in dorsal horn NKCC1 phosphorylation (Star A) and an increase in NKCC1 in the cell membrane (Star B). It is not known if nociceptor spiking associated with this stimulus also contributes to an increase in NKCC1 activity in the dorsal horn (Star C).

Publication

Chloride Regulation in the Pain Pathway. () Theodore J Price, et al. Brain Res Rev. ;60(1):149-170. Figure: F4. Homo sapiens

Disease mentions