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Neurotransmitters responsible for purinergic motor neurotransmission and regulation of GI motility

      Highlights

      • Recent advances on the concept that ATP or related purines act as motor neurotransmitters in the enteric nervous system are discussed in this review.
      • Post-junctional cells that transduce purinergic neurotransmitters in gastrointestinal muscles are PDGFRa+ cells and not smooth muscle cells.
      • P2Y1 receptor agonists activate Ca2+ release and small conductance Ca2+-activated potassium channels in PDGFRa+ cells. SK channels cause hyperpolarization that is conducted to smooth muscle cells and inhibition of contraction.
      • P2Y1 receptor agonists activate Ca2+ release and small conductance Ca2+-activated potassium channels in PDGFRα+ cells.
      • Refinements in techniques to measure purines released during neurotransmission have shown that multiple purines are released by enteric neurons. β-NAD+ and other purines, better satisfy criteria for the enteric purinergic neurotransmitter than ATP.
      • Evaluation of purine metabolites have shed new light on the cells and enzymes responsible for deactivation of purinergic inhibitory effects.

      Abstract

      Classical concepts of peripheral neurotransmission were insufficient to explain enteric inhibitory neurotransmission. Geoffrey Burnstock and colleagues developed the idea that ATP or a related purine satisfies the criteria for a neurotransmitter and serves as an enteric inhibitory neurotransmitter in GI muscles. Cloning of purinergic receptors and development of specific drugs and transgenic mice have shown that enteric inhibitory responses depend upon P2Y1 receptors in post-junctional cells. The post-junctional cells that transduce purinergic neurotransmitters in the GI tract are PDGFRα+ cells and not smooth muscle cells (SMCs). PDGFRα+ cells express P2Y1 receptors, are activated by enteric inhibitory nerve stimulation and generate Ca2+ oscillations, express small-conductance Ca2+-activated K+ channels (SK3), and generate outward currents when exposed to P2Y1 agonists. These properties are consistent with post-junctional purinergic responses, and similar responses and effectors are not functional in SMCs. Refinements in methodologies to measure purines in tissue superfusates, such as high-performance liquid chromatography (HPLC) coupled with etheno-derivatization of purines and fluorescence detection, revealed that multiple purines are released during stimulation of intrinsic nerves. β-NAD+ and other purines, better satisfy criteria for the purinergic neurotransmitter than ATP. HPLC has also allowed better detection of purine metabolites, and coupled with isolation of specific types of post-junctional cells, has provided new concepts about deactivation of purine neurotransmitters. In spite of steady progress, many unknowns about purinergic neurotransmission remain and require additional investigation to understand this important regulatory mechanism in GI motility.

      Keywords

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