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Abstract
Trans-synaptic regulation of muscarinic, peptidergic, and purinergic responses after denervation has been reported previously in rat parotid acinar cells (McMillian, M. K., Soltoff, S. P., Cantley, L. C., Rudel, R., and Talamo, B. R. (1993) Br. J. Pharmacol. 108, 453-461). Characteristics of the ATP-mediated responses and the effects of parasympathetic denervation were further analyzed through assay of Ca2+ influx, using fluorescence ratio imaging methods, and by analysis of P2x receptor expression. ATP activates both a high affinity and a low affinity response with properties corresponding to the recently described P2x4 and the P2z (P2x7)-type purinoceptors, respectively. Reverse transcription-polymerase chain reaction analysis reveals mRNA for P2x4 as well as P2x7 subtypes but not P2x1, P2x2, P2x3, P2x5, or P2x6. P2x4 protein also is detected by Western blotting. Distribution of the two types of ATP receptor responses on individual cells was stochastic, with both high and low affinity responses on some cells, and only a single type of response on others. Sensitivity to P2x4-type activation also varied even among cells responsive to low concentrations of ATP. Parasympathetic denervation greatly enhanced responses, tripling the proportion of acinar cells with a P2x4-type response and increasing the fraction of highly sensitive cells by 7-fold. Moreover, P2x4 mRNA is significantly increased following parasympathetic denervation. These data indicate that sensitivity to ATP is modulated by neurotransmission at parasympathetic synapses, at least in part through increased expression of P2x4 mRNA, and suggest that similar regulation may occur at other sites in the nervous system where P2x4 receptors are widely expressed.
Highlights
Extracellular ATP acts as a signaling molecule through the interaction of ATP with ligand-gated ion channels (P2x) as well as metabotropic receptors (P2y)
We have shown that removal of the autonomic innervation alters ATP responses in parotid acinar cells, which provide a good model for investigating trans-synaptic regulation of receptor-mediated signaling
We previously described two ATP responses in rat parotid acinar cells, a P2z/x7 type and a high affinity ATP receptor with distinctly different P2x-like pharmacology [1]
Summary
We previously described two ATP responses in rat parotid acinar cells, a P2z/x7 type and a high affinity ATP receptor with distinctly different P2x-like pharmacology [1]. Our previous denervation studies established that trans-synaptic regulation of sensitivity to these neurotransmitters can be demonstrated in vitro in dissociated cell suspensions and showed for the first time that sensitivity to ATP is increased very dramatically [1, 31]. This suggests that P2x purinoceptors are modulated by changes in synaptic activity and that ATP plays a role in the physiologically important regulation of food intake and metabolism. P2x1 P2x2 P2x3 P2x4 (up/lo) P2x4 (A/B) P2x4 (A/Far) P2x5 P2x6 P2x7 (Trunc) P2x7 (C-term) P2x7 (3Ј-UTR) GAPDH
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