Abstract
The ionotropic P2X receptor, P2X7, is believed to regulate and/or generate nociceptive pain, and pain in several neuropathological diseases. Although there is a known relationship between P2X7 receptor activity and pain sensing, its detailed functional properties in trigeminal ganglion (TG) neurons remains unclear. We examined the electrophysiological and pharmacological characteristics of the P2X7 receptor and its functional coupling with other P2X receptors and pannexin-1 (PANX1) channels in primary cultured rat TG neurons, using whole-cell patch-clamp recordings. Application of ATP and Bz-ATP induced long-lasting biphasic inward currents that were more sensitive to extracellular Bz-ATP than ATP, indicating that the current was carried by P2X7 receptors. While the biphasic current densities of the first and second components were increased by Bz-ATP in a concentration dependent manner; current duration was only affected in the second component. These currents were significantly inhibited by P2X7 receptor antagonists, while only the second component was inhibited by P2X1, 3, and 4 receptor antagonists, PANX1 channel inhibitors, and extracellular ATPase. Taken together, our data suggests that autocrine or paracrine signaling via the P2X7-PANX1-P2X receptor/channel complex may play important roles in several pain sensing pathways via long-lasting neuronal activity driven by extracellular high-concentration ATP following tissue damage in the orofacial area.
Highlights
P2 purinergic receptors can be classified into P2X and P2Y receptors, which are further divided into seven subtypes (P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7 ) of ligand-gated cation channels and eight subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14 ) of
The current–voltage (I-V) relationships, which were determined by plotting the peak current amplitudes in the densities against the applied membrane potentials, were measured by applying 20-ms voltage steps ranging from −80 to +100 mV at 2-s intervals (Figure 1A,B)
To investigate which P2X receptors contributed to the biphasic inward current inTo investigate which P2X receptors contributed to the biphasic inward current induced duced by Bz-Adenosine triphosphate (ATP), we examined the effects of the non-specific P2X receptor antagonist by Bz-ATP, we examined the effects of the non-specific P2X receptor antagonist (PPADS), (PPADS), the P2X1 receptor antagonist (NF449), the P2X3 receptor antagonist (NF110), the the P2X1 receptor antagonist (NF449), the P2X3 receptor antagonist (NF110), the P2X4
Summary
Adenosine triphosphate (ATP), which is generated intracellularly, plays important roles in both physiological and pathological cellular functions including the extracellular mediator, such as nociceptive, inflammatory, and neuropathic pain as well as migraine- and cancer-induced pain [1,2,3]. ATP acts on P2 purinergic receptors, which are cell-surface nucleotide receptors [4]. Among the P2 purinergic receptors, P2X30 s involvement in nociceptive pain was first reported in the tooth-pulp afferents of trigeminal ganglion (TG) neurons [1]. While protein and/or mRNA expression of P2X1 –6 , and P2Y12 receptors has been reported in TG neurons [5,6,7,8,9,10], the detailed functional electrophysiological and pharmacological properties of P2X7 receptors in TG neurons has yet to be examined
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