Abstract
Polyamines are important endogenous regulators of ion channels and are known to modulate inflammation and nociception. Here we investigated effects of polyamines on the capsaicin receptor TRPV1, a major ion channel expressed in nociceptive sensory afferents. Extracellular spermine, spermidine, and putrescine directly activated TRPV1 in a charge-dependent manner, both in heterologous expression systems and sensory neurons. The threshold for activation by spermine was approximately 500 microm at room temperature. At lower concentrations, spermine enhanced capsaicin-evoked currents with an EC50 of approximately 5 microm. Further, polyamines freely permeated TRPV1 (estimated relative permeabilities compared with Na+ were between 3 and 16), and spermine reduced the single channel conductance from 96 to 49 pS. Experiments with TRPV1 mutants identified extracellular acidic residues critical for polyamine regulation. Neutralization of aspartate 646 (D646N) abolished direct activation by spermine, whereas neutralization of this same aspartate (D646N) or glutamate 648 (E648A) inhibited spermine-induced sensitization. These data show that polyamines, by virtue of their cationic charge, can regulate the activity of TRPV1. Extracellular polyamines are present in considerable concentrations in the gastrointestinal tract and at synapses, and these levels increase during inflammation and cancer. Therefore, polyamine regulation of TRPV1 in these tissues may be relevant to a variety of physiological and pathophysiological states.
Highlights
Polyamines are known to regulate inflammation and pain signaling
Polyamines Activate TRPV1 in HEK293 Cells and Oocytes—We examined the effects of spermine on the function of TRPV1 expressed in HEK293 cells
This study has identified polyamines as novel regulators of TRPV1 channel activity
Summary
Polyamines are known to regulate inflammation and pain signaling. Levels of polyamines are raised during infection, trauma, and cancer [12], and intrathecal administration of spermine in mice produces nocifensive behaviors (i.e. scratching, licking, and biting) characteristic of noxious stimuli [13]. TRPV1 is regulated by protons [14, 15] and by extracellular cations including Naϩ, Mg2ϩ, and Ca2ϩ [16]. These cations sensitize TRPV1 to ligand activation, and divalent cations (Ͼ5 mM) directly activate the receptor and induce painrelated behaviors in mice [16]. Spermine potently sensitizes TRPV1, enhancing capsaicin responses with an EC50 of ϳ5 M, a concentration that falls within the range of normal serum levels [17]. These responses are abolished in TRPV1 mutants lacking key acidic residues near the extracellular pore-forming region. Extracellular polyamines may represent a new class of endogenous TRPV1 ligands
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
