Kinesin Nanomotors Mediated Trafficking of NMDA-Loaded Cargo as A Novel Target in Chronic Pain

Abstract

Chronic pain is among the most prevalent burdensome disorders worldwide. The N-methyl-d-aspartate (NMDA) receptor system plays a critical role in central sensitization, a primary feature of chronic pain. Despite the proven efficacy of exogenous ligands to this receptor system in preclinical studies, evidence for the clinical efficacy of NMDA antagonists for the treatment of chronic pain is weak. Researchers are studying alternate approaches, rather than direct inhibition of the NMDA receptors in pain processing neurons. This indirect approach utilizes the modulation of molecular switches that regulates the synthesis, maturation, and transport of receptors from cellular organelles to the synaptic membrane. Kinesins are nanomotors that anterogradely transport the cargo using microtubule tracks across the neurons. Various members of the kinesin family, including KIF17, KIF11, KIF5b, and KIF21a, regulate the intracellular transport of NMDA receptors. Pharmacological targeting of these ATP-driven nanomotors could be a useful tool for manipulating the NMDAR functioning. It could provide the potential for the development of a novel strategy for the management of chronic pain.

Keywords: Cargo binding; Chronic pain; KIF17; Kinesin nanomotors; NR2B; mLin-10.