Nitrergic and purinergic mechanisms evoke inhibitory neuromuscular transmission in the human small intestine

Gallego, Diana; Malagelada, Carolina; Accarino, Anna; Giorgio, Roberto De; Malagelada, Juan–R.; Azpiroz, Fernando; Jiménez, Marcel

doi:10.1111/nmo.12293

Cited by 29 publications

(55 citation statements)

References 39 publications

(91 reference statements)

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“…Some purines can act pre-synaptically to inhibit ATP release in the human jejunum (52). These nucleotides may also play a role at the post-synaptic level by desensitizing the P2Y 1 receptor, as has been shown in the human small bowel and colon (24)(25)(26)30,36). Experimental models of colitis showing a decreased purinergic IJP component (IJPf) confirm this hypothesis.…”

Section: Contractionsupporting

confidence: 58%

“…Purinergic receptors are present in numerous cell types since purines play a role in many cell com- Suramin and PPADs are scarcely selective purinergic antagonists that do not allow differentiation between distinct P2 receptors. The development of specific antagonists such as, for instance MRS2179, which blocks P2Y1 receptors (34;35), allowed to identify pharmacologically that ATP, acts post-junctionally through P2Y1 receptors causing smooth muscle relaxation in several GI tract areas (12,24,25,36,37). Subsequently, two new antagonists (MRS2279 and MRS2500) with greater affinity for the P2Y1 receptor, (35,38,39) confirmed the crucial role of this receptor subtype in purinergic neurotransmission.…”

Section: P2y 1 Receptor Identified As Responsible For Bowel Relaxationmentioning

confidence: 98%

“…In contrast. In contrast ATP may have a key role in transient relaxation as is, for instance, the case with the descending phase of the peristaltic reflex (24,26), and would therefore predominate in areas with more relevant peristalsis, including the small intestine and colon (17,19,24,25,30,36,37).…”

Section: Functional No-atp Co-transmissionmentioning

confidence: 99%

“…Recent studies from our laboratory show that the effect of both neurotransmitters depends on the frequency of nerve stimulation of the preparation (24)(25)(26). At low frequencies (below 1 Hz) purinergic response predominates, whereas higher frequencies attenuate purinergic responses and increase the nitrergic ones (26) (Fig.…”

Section: Functional No-atp Co-transmissionmentioning

confidence: 99%

“…This hyperpolarization is responsible for sustained mechanical relaxation. Furthermore, NO is tonically released, and is held responsible for the so-called inhibitory inhibitory neural tone (24)(25)(26).…”

Section: Receptor and Intracellular Pathwaymentioning

confidence: 99%

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Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

Gallego¹,

Mañé²,

Gil³

et al. 2016

Rev Esp Enferm Dig

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The enteric nervous system (ENS) is responsible for the genesis of motor patterns ensuring an appropriate intestinal transit. Enteric motor neurons are classified into afferent neurons, interneurons and motorneurons. Motorneurons are excitatory or inhibitory causing smooth muscle contraction and relaxation respectively. Muscle relaxation mechanisms are key for the understanding of physiological processes such as sphincter relaxation, gastric accommodation, or the descending phase of the peristaltic reflex. Nitric oxide (NO) and ATP or a related purine are the primary inhibitory neurotransmitters. Nitrergic neurons synthesize NO through nNOS enzyme activity. NO diffuses across the cell membrane to bind guanylyl cyclase, and then activates a number of intracellular mechanisms that ultimately result in muscle relaxation. ATP is an inhibitory neurotransmitter together with NO. The P2Y1 receptor has been identified as a the purine receptor responsible for smooth muscle relaxation. Although, probably, no clinician doubts about the significance of NO in the pathophysiology of gastrointestinal motility, the relevance of purinergic neurotransmission is apparently much lower, as ATP has not been associated with any specific motor dysfunction yet. The goal of this review is to discuss the function of both relaxation mechanisms in order to establish the physiological grounds of potential motor dysfunctions arising from impaired intestinal relaxation.

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Section: Contractionsupporting

confidence: 58%

Section: P2y 1 Receptor Identified As Responsible For Bowel Relaxationmentioning

confidence: 98%

Section: Functional No-atp Co-transmissionmentioning

confidence: 99%

Section: Functional No-atp Co-transmissionmentioning

confidence: 99%

Section: Receptor and Intracellular Pathwaymentioning

confidence: 99%

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Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

Gallego¹,

Mañé²,

Gil³

et al. 2016

Rev Esp Enferm Dig

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Development of Gastrointestinal Motility Reflexes

Viswanathan¹,

Jadcherla²

2019

Gastroenterology and Nutrition

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ATP as a cotransmitter in the autonomic nervous system

Kennedy¹

2015

Autonomic Neuroscience

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The role of adenosine 5'-triphosphate (ATP) as a major intracellular energy source is well-established. In addition, ATP and related nucleotides have widespread extracellular actions via the ionotropic P2X (ligand-gated cation channels) and metabotropic P2Y (G protein-coupled) receptors. Numerous experimental techniques, including myography, electrophysiology and biochemical measurement of neurotransmitter release, have been used to show that ATP has several major roles as a neurotransmitter in peripheral nerves. When released from enteric nerves of the gastrointestinal tract it acts as an inhibitory neurotransmitter, mediating descending muscle relaxation during peristalsis. ATP is also an excitatory cotransmitter in autonomic nerves; 1) It is costored with noradrenaline in synaptic vesicles in postganglionic sympathetic nerves innervating smooth muscle preparations, such as the vas deferens and most arteries. When coreleased with noradrenaline, ATP acts at postjunctional P2X1 receptors to evoke depolarisation, Ca(2+) influx, Ca(2+) sensitisation and contraction. 2) ATP is also coreleased with acetylcholine from postganglionic parasympathetic nerves innervating the urinary bladder and again acts at postjunctional P2X1 receptors, and possibly also a P2X1+4 heteromer, to elicit smooth muscle contraction. In both cases the neurotransmitter actions of ATP are terminated by dephosphorylation by extracellular, membrane-bound enzymes and soluble nucleotidases released from postganglionic nerves. There are indications of an increased contribution of ATP to control of blood pressure in hypertension, but further research is needed to clarify this possibility. More promising is the upregulation of P2X receptors in dysfunctional bladder, including interstitial cystitis, idiopathic detrusor instability and overactive bladder syndrome. Consequently, these roles of ATP are of great therapeutic interest and are increasingly being targeted by pharmaceutical companies.

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Nitrergic and purinergic mechanisms evoke inhibitory neuromuscular transmission in the human small intestine

Abstract: Similar to colon, inhibitory neurotransmission in the human small intestine is mainly mediated by purinergic (via P2Y1 receptors) and nitrergic inhibitory neurotransmission. Similar mechanisms of inhibitory neurotransmission are present in different regions of the human intestine.

Cited by 29 publications

References 39 publications

Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

Development of Gastrointestinal Motility Reflexes

ATP as a cotransmitter in the autonomic nervous system

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