Plasma gelsolin protects HIV-1 gp120-induced neuronal injury via voltage-gated K+ channel Kv2.1

Abstract

Plasma gelsolin (pGSN), a secreted form of gelsolin, is constitutively expressed throughout the central nervous system (CNS). Neurons, astrocytes and oligodendrocytes are the major sources of pGSN in the CNS. It has been shown that levels of pGSN in cerebrospinal fluid (CSF) are decreased in several neurological conditions including HIV-1-associated neurocognitive disorders (HAND). Although there is no direct evidence that a decreased level of pGSN in CSF is causally related to the pathogenesis of neurological disorders, neural cells, if lacking pGSN, are more vulnerable to cell death. To understand how GSN levels relate to neuronal injury in HAND, we studied the effects of pGSN on HIV-1 gp120-activated outward K+ currents in primary rat cortical neuronal cultures. Incubation of rat cortical neurons with gp120 enhanced the outward K+ currents induced by voltage steps and resulted in neuronal apoptosis. Treatment with pGSN suppressed the gp120-induced increase of delayed rectifier current (IK) and reduced vulnerability to gp120-induced neuronal apoptosis. Application of Guangxitoxin-1E (GxTx), a Kv2.1 specific channel inhibitor, inhibited gp120 enhancement of IK and associated neuronal apoptosis, similar effects to pGSN. Western blot and PCR analysis revealed gp120 exposure to up-regulate Kv2.1 channel expression, which was also inhibited by treatment with pGSN. Taken together, these results indicate pGSN protects neurons by suppressing gp120 enhancement of IK through Kv2.1 channels and reduction of pGSN in HIV-1-infected brain may contribute to HIV-1-associated neuropathy.

SP6616 as a new Kv2.1 channel inhibitor efficiently promotes β-cell survival involving both PKC/Erk1/2 and CaM/PI3K/Akt signaling pathways

“…For example, peptide-type inhibitors include hanatoxin, guangxitoxin-1E, heteroscordratoxins, ScTx-1, SGTx1, syntaxin-1A, SsmTx-I and plasma gelsolin. 30 , 31 , 32 , 33 , 34 , 35 , 36 Small molecular inhibitors galantamine and isoliquiritigenin block Kv2.1 currents with little data on GSIS or cell apoptosis; 37 , 38 RY796 and C-1 enhance GSIS; 8 , 9 donepezil and 48F10 abolish neuronal apoptosis. 39 , 40 Previously, we reported natural product vindoline functioned in promotion of both insulin secretion and β -cell protection.…”

Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

“…Some of these proteins stand out among the others because their functions have been shown to be essential for neuronal function. For example, gelsolin (with two isoforms, one secreted-86 kDa and other cytoplasmic-81 kDa), is a calcium-regulated severing protein recognized by its neuroprotective activity [78][79][80]. Drebrin (48 kDa) binds to F-actin in dendritic spines changing its properties [81].…”

Proteomic analysis of cerebrospinal fluid in California sea lions (Zalophus californianus) with domoic acid toxicosis identifies proteins associated with neurodegeneration

“…Gelsolin regulates the influx of calcium through voltage‐dependent calcium channels and NMDA receptors, and counters the toxicity of glutamate in mouse hippocampal neurons . Exogenously administered plasma gelsolin was found to reduce infarct volume in an experimental rat model of ischemic stroke , attenuate caspase‐3 activity in the brain of mice following burn injury , and reduce neuronal injury due to HIV gp‐120 . Exogenous administration of gelsolin was also found to increase the integrity of the blood‐cerebrospinal fluid barrier at the choroid .…”