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NEUROREGULATION AND MOTILITY

Dual purinergic synaptic transmission in the human enteric nervous system

Departments of ¹Anesthesiology, ²Neuroscience, and ³Surgery, Division of GI Surgery, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio

Submitted 30 October 2007 ; accepted in final form 13 December 2007

Based on findings in rodents, we sought to test the hypothesis that purinergic modulation of synaptic transmission occurs in the human intestine. Time series analysis of intraneuronal free Ca²⁺ levels in submucosal plexus (SMP) from Roux-en-Y specimens was done using Zeiss LSM laser-scanning confocal fluo-4 AM Ca²⁺ imaging. A 3-s fiber tract stimulation (FTS) was used to elicit a synaptic Ca²⁺ response. Short-circuit current (I_sc = chloride secretion) was recorded in mucosa-SMP in flux chambers. A distension reflex or electrical field stimulation was used to study I_sc responses. Ca²⁺ imaging was done in 1,222 neurons responding to high-K⁺ depolarization from 61 surgical cases. FTS evoked synaptic Ca²⁺ responses in 62% of recorded neurons. FTS caused frequency-dependent Ca²⁺ responses (0.1–100 Hz). FTS Ca²⁺ responses were inhibited by -conotoxin (70%), hexamethonium (50%), TTX, high Mg²⁺/low Ca²⁺ (100%), or capsaicin (25%). A P2Y₁ receptor (P2Y₁R) antagonist, MRS-2179 or PLC inhibitor U-73122, blocked FTS responses (75–90%). P2Y₁R-immunoreactivity occurred in 39% of vasoactive intestinal peptide-positive neurons. The selective adenosine A₃ receptor (AdoA₃R) agonist 2-chloro-N⁶-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (2-Cl-IBMECA) caused concentration- and frequency-dependent inhibition of FTS Ca²⁺ responses (IC₅₀ = 8.5 x 10^–8 M). The AdoA₃R antagonist MRS-1220 augmented such Ca²⁺ responses; 2-Cl-IBMECA competed with MRS-1220. Knockdown of AdoA₁R with 8-cyclopentyl-3-N-(3-{[3-(4-fluorosulphonyl)benzoyl]-oxy}-propyl)-1-N-propyl-xanthine did not prevent 2-Cl-IBMECA effects. MRS-1220 caused 31% augmentation of TTX-sensitive distension I_sc responses. The SMP from Roux-en-Y patients is a suitable model to study synaptic transmission in human enteric nervous system (huENS). The P2Y₁/Gq/PLC/inositol 1,3,5-trisphosphate/Ca²⁺ signaling pathway, N-type Ca²⁺ channels, nicotinic receptors, and extrinsic nerves contribute to neurotransmission in huENS. Inhibitory AdoA₃R inhibit nucleotide or cholinergic transmission in the huENS.

purinergic transmission; calcium signaling; adenosine A₃ receptors; P2Y₁ receptors; submucous nerve plexus

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