Abstract
ABSTRACTSpecialized microdomains which have cholesterol-rich membrane regions contain transient receptor potential vanilloid subtype 1 (TRPV1) are involved in pain development. Our previous studies have demonstrated that the depletion of prostatic acid phosphatase (PAP) – a membrane-bound ectonucleotidase – and disordered adenosine signaling reduce the antinociceptive effect. The role of membrane integrity in the PAP-mediated antinociceptive effect in small-fiber neuropathy remains unclear, especially with respect to whether TRPV1 and PAP are colocalized in the same microdomain which is responsible for PAP-mediated antinociception. Immunohistochemistry was conducted on the dorsal root ganglion to identify the membrane compositions, and pharmacological interventions were conducted using methyl-β-cyclodextrin (MβC) – a membrane integrity disruptor that works by depleting cholesterol – in pure small-fiber neuropathy with resiniferatoxin (RTX). Immunohistochemical evidence indicated that TRPV1 and PAP were highly colocalized with flotillin 1 (66.7%±9.7%) and flotillin 2 (73.7%±6.0%), which reside in part in the microdomain. MβC mildly depleted PAP, which maintained the ability to hydrolyze phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and delayed the development of mechanical allodynia. MβC treatment had no role in thermal transduction and neuronal injury following RTX neuropathy. In summary, this study demonstrated the following: (1) membrane cholesterol depletion preserves PAP-mediated antinociception through PI(4,5)P2 hydrolysis and (2) pain hypersensitivity that develops after TRPV1(+) neuron depletion-mediated neurodegeneration following RTX neuropathy is attributable to the downregulation of PAP analgesic signaling.
Highlights
A specialized microdomain which has cholesterol-rich membrane regions contains several transmembrane molecules that modulate cellular physiology
Profiling membrane compositions in RTX neuropathy Triple-labeling immunofluorescence staining was performed to assess the colocalization of transient receptor potential vanilloid subtype 1 (TRPV1) and prostatic acid phosphatase (PAP) with FLOT1 (Fig. 2A, D,E,H) and FLOT2 (Fig. 2I,L,M,P), which reside in part in microdomains
The results showed that 67% of TRPV1 and PAP colocalized with FLOT1 and 74% with FLOT2 (Fig. 2S)
Summary
A specialized microdomain which has cholesterol-rich membrane regions contains several transmembrane molecules that modulate cellular physiology. Disrupting the membrane integrity causes distinct effects such as reversing the cytotoxicity of antitumor drugs (Adinolfi et al, 2013), antagonizing hyperalgesia (Dina et al, 2005) and inhibiting endocannabinoid-mediated analgesic systems (Rossi et al, 2012). These effects imply that microdomains may affect neuronal regulation, in neuronal antinociception. Research is necessary to determine whether a transmembrane molecule exists that colocalizes and interacts with PAP in an integrity of membrane structure to modulate PAPmediated antinociception. Transient receptor potential vanilloid subtype 1 (TRPV1) is a candidate because PAP mediates antinociception by reducing TRPV1 activity (Sowa et al, 2010), and TRPV1-mediated nociception requires TRPV1 on membrane integrity (Marchenkova et al, 2016; Saghy et al, 2015; Szőke et al, 2010)
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