Regulation of TRPV1 channel activities by intracellular ATP in the absence of capsaicin

Capsaicin is a potent agonist of the TRPV1 channel, a transduction channel that is highly expressed in nociceptive fibers (pain fibers) throughout the peripheral nervous system. Given the importance of TRPV1 as one of several transduction channels in nociceptive fibers, much research has been focused on the potential therapeutic benefits of using TRPV1 antagonists for the management of pain. However, an antagonist has two limitations. First, an antagonist in principle generally only affects one receptor. Secondly, most antagonists must have an ongoing presence on the receptor to have an effect. Capsaicin overcomes both liabilities by disrupting peripheral terminals of nociceptive fibers that express TRPV1, and thereby affects all of the potential means of activating that pain fiber (not just TRPV1 function). This disruptive effect is dependent on the dose and can occur within minutes. Thus, unlike a typical receptor antagonist, continued bioavailability at the level of the receptor is not necessary. By disrupting the entire terminal of the TRPV1-expressing nociceptive fiber, capsaicin blocks all the activation mechanisms within that fiber, and not just TRPV1 function. Topical capsaicin, an FDA approved treatment for neuropathic pain, addresses pain from abnormal nociceptor activity in the superficial layers of the skin. Effects after a single administration are evident over a period of weeks to months, but in time are fully reversible. This review focuses on the rationale for using capsaicin by injection for painful conditions such as osteoarthritis (OA) and provides an update on studies completed to date.

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Intracellular ATP Increases Capsaicin-Activated Channel Activity by Interacting with Nucleotide-Binding Domains

Journal of Neuroscience ◽

10.1523/jneurosci.20-22-08298.2000 ◽

2000 ◽

Vol 20 (22) ◽

pp. 8298-8304 ◽

Cited By ~ 45

Author(s):

Jiyeon Kwak ◽

Myeong Hyeon Wang ◽

Sun Wook Hwang ◽

Tae-Yoon Kim ◽

Soon-Youl Lee ◽

...

Keyword(s):

Nucleotide Binding ◽

Channel Activity ◽

Intracellular Atp ◽

Binding Domains

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Proximal tubule dysfunction in cystine-loaded tubules: effect of phosphate and metabolic substrates

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.3.f717 ◽

1996 ◽

Vol 271 (3) ◽

pp. F717-F722

Author(s):

G. Bajaj ◽

M. Baum

Keyword(s):

Oxygen Consumption ◽

Proximal Tubule ◽

Tricarboxylic Acid Cycle ◽

Dimethyl Ester ◽

Proximal Tubules ◽

Intracellular Atp ◽

Metabolic Substrates ◽

Rate Of Oxygen Consumption ◽

Intracellular Phosphate

Intracellular cystine loading by use of cystine dimethyl ester (CDME) results in a generalized inhibition in proximal tubule transport due, in part, to a decrease in intracellular ATP. The present study examined the importance of phosphate and metabolic substrates in the proximal tubule dysfunction produced by cystine loading. Proximal tubule intracellular phosphorus was 1.8 +/- 0.1 in control tubules and 1.1 +/- 0.1 nmol/mg protein in proximal tubules incubated in vitro with CDME P < 0.001). Infusion of sodium phosphate in rabbits and subsequent incubation of proximal tubules with a high-phosphate medium attenuated the decrease in proximal tubule respiration and prevented the decrease in intracellular ATP with cystine loading. Tricarboxylic acid cycle intermediates have been shown to preserve oxidative metabolism in phosphate-depleted proximal tubules. In proximal tubules incubated with either 1 mM valerate or butyrate, there was a 42 and 34% reduction (both P < 0.05) in the rate of oxygen consumption with cystine loading. However, tubules incubated with 1 mM succinate or citrate had only a 13 and 14% P = NS) reduction in the rate of oxygen consumption, respectively. These data are consistent with a limitation of intracellular phosphate in the pathogenesis of the proximal tubule dysfunction with cystine loading.

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Improved Antimicrobial Activities of Synthetic-Hybrid Bacteriocins Designed from Enterocin E50-52 and Pediocin PA-1

Applied and Environmental Microbiology ◽

10.1128/aem.03477-14 ◽

2014 ◽

Vol 81 (5) ◽

pp. 1661-1667 ◽

Cited By ~ 20

Author(s):

Santosh Kumar Tiwari ◽

Katia Sutyak Noll ◽

Veronica L. Cavera ◽

Michael L. Chikindas

Keyword(s):

Micrococcus Luteus ◽

Electrical Potential ◽

Gram Negative Bacteria ◽

Additional Advantage ◽

Gram Negative ◽

Content Type ◽

Intracellular Atp ◽

Hybrid Peptides ◽

C Terminus ◽

N Terminus

ABSTRACTTwo hybrid bacteriocins, enterocin E50-52/pediocin PA-1 (EP) and pediocin PA-1/enterocin E50-52 (PE), were designed by combining the N terminus of enterocin E50-52 and the C terminus of pediocin PA-1 and by combining the C terminus of pediocin PA-1 and the N terminus of enterocin E50-52, respectively. Both hybrid bacteriocins showed reduced MICs compared to those of their natural counterparts. The MICs of hybrid PE and EP were 64- and 32-fold lower, respectively, than the MIC of pediocin PA-1 and 8- and 4-fold lower, respectively, than the MIC of enterocin E50-52. In this study, the effect of hybrid as well as wild-type (WT) bacteriocins on the transmembrane electrical potential (ΔΨ) and their ability to induce the efflux of intracellular ATP were investigated. Enterocin E50-52, pediocin PA-1, and hybrid bacteriocin PE were able to dissipate ΔΨ, but EP was unable to deplete this component. Both hybrid bacteriocins caused a loss of the intracellular concentration of ATP. EP, however, caused a faster efflux than PE and enterocin E50-52. Enterocin E50-52 and hybrids PE and EP were active against the Gram-positive and Gram-negative bacteria tested, such asMicrococcus luteus,Salmonella entericaserovar Enteritidis 20E1090, andEscherichia coliO157:H7. The hybrid bacteriocins designed and described herein are antimicrobial peptides with MICs lower those of their natural counterparts. Both hybrid peptides induce the loss of intracellular ATP and are capable of inhibiting Gram-negative bacteria, and PE dissipates the electrical potential. In this study, the MIC of hybrid bacteriocin PE decreased 64-fold compared to the MIC of its natural peptide counterpart, pediocin PA-1. Inhibition of Gram-negative pathogens confers an additional advantage for the application of these peptides in therapeutics.

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