Loss of Nucleotide Regulation of Epithelial Chloride Transport in the Jejunum of P2Y 4 -Null Mice

Secretomotor reflexes in the gastrointestinal (GI) tract are important in the lubrication and movement of digested products, absorption of nutrients, or the diarrhea that occurs in diseases to flush out unwanted microbes. Mechanical or chemical stimulation of mucosal sensory enterochromaffin (EC) cells triggers release of serotonin (5-HT) (among other mediators) and initiates local reflexes by activating intrinsic primary afferent neurons of the submucous plexus. Signals are conveyed to interneurons or secretomotor neurons to stimulate chloride and fluid secretion. Inputs from myenteric neurons modulate secretory rates and reflexes, and special neural circuits exist to coordinate secretion with motility. Cellular components of secretomotor reflexes variably express purinergic receptors for adenosine (A1, A2a, A2b, or A3 receptors) or the nucleotides adenosine 5′-triphosphate (ATP), adenosine diphosphate (ADP), uridine 5′-triphosphate (UTP), or uridine diphosphate (UDP) (P2X 1-7 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 12 receptors). This review focuses on the emerging concepts in our understanding of purinergic regulation at these receptors, and in particular of mechanosensory reflexes. Purinergic inhibitory (A 1 , A 3 , P2Y 12 ) or excitatory (A 2 , P2Y 1 ) receptors modulate mechanosensitive 5-HT release. Excitatory (P2Y 1 , other P2Y, P2X) or inhibitory (A 1 , A 3 ) receptors are involved in mechanically evoked secretory reflexes or "neurogenic diarrhea." Distinct neural (pre-or postsynaptic) and non-neural distribution profiles of P2X 2 , P2X 3 , P2X 5 , P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , or P2Y 12 receptors, and for some their effects on neurotransmission, suggests their role in GI secretomotor function. Luminal A 2b , P2Y 2 , P2Y 4 , and P2Y 6 receptors are involved in fluid and Cl -, HCO 3 -, K + , or mucin secretion. Abnormal receptor expression in GI diseases may be of clinical relevance. Adenosine A 2a or A 3 receptors are emerging as therapeutic targets in inflammatory bowel diseases (IBD) and gastroprotection; they can also prevent purinergic receptor abnormalities and diarrhea. Purines are emerging as fundamental regulators of enteric secretomotor reflexes in health and disease.

Section: Enac and Cftr Channelsmentioning

confidence: 99%

Section: Enac and Cftr Channelsmentioning

confidence: 99%

Section: Enac and Cftr Channelsmentioning

confidence: 99%

See 1 more Smart Citation

Purinergic receptors and gastrointestinal secretomotor function

Christofi

2008

“…Differential effects of apical and basolateral UTP on intestinal epithelial Cl − secretion have been described [626]. There is a loss of regulation of Cl − transport by ATP and UTP in the jejunum of P2Y 4 -null mice [580]. Cuthbert and Hickman [165] confirmed the earlier reports about the effects of ATP on transepithelial ion transport but, since they found that TTX virtually abolished the effects of ATP on electrogenic chloride secretion, they suggested that the effects of ATP were indirect, via neural elements in the intramural plexus.…”

Section: Intestinal Secretionmentioning

confidence: 99%

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

Burnstock

2013

Purinergic signalling plays major roles in the physiology and pathophysiology of digestive organs. Adenosine 5′-triphosphate (ATP), together with nitric oxide and vasoactive intestinal peptide, is a cotransmitter in nonadrenergic, non-cholinergic inhibitory neuromuscular transmission. P2X and P2Y receptors are widely expressed in myenteric and submucous enteric plexuses and participate in sympathetic transmission and neuromodulation involved in enteric reflex activities, as well as influencing gastric and intestinal epithelial secretion and vascular activities. Involvement of purinergic signalling has been identified in a variety of diseases, including inflammatory bowel disease, ischaemia, diabetes and cancer. Purinergic mechanosensory transduction forms the basis of enteric nociception, where ATP released from mucosal epithelial cells by distension activates nociceptive subepithelial primary afferent sensory fibres expressing P2X3 receptors to send messages to the pain centres in the central nervous system via interneurons in the spinal cord. Purinergic signalling is also involved in salivary gland and bile duct secretion.

“…Using a knockout model for the P2Y2 receptor, Cressman et al demonstrated impaired Cl − secretion in airway and gallbladder epithelium, but not in tissue from the jejunum [47]. Other receptors have also been shown to regulate chloride conductance including P2Y4 in intestinal epithelia [48,49] and the UDP receptor P2Y6 in bronchial epithelium [50]. P2Y2 receptor-induced Cl − secretion results from increased intracellular Ca 2+ concentration leading to activation of Ca 2+ -activated Cl − channels.…”

Section: Chloride Secretionmentioning

confidence: 99%

The touching story of purinergic signaling in epithelial and endothelial cells

Öhman

Erlinge

2012

Endothelial and epithelial cells have something in commonthey are both the barrier and bridge between different environments. Forming a one-cell layer lining of blood vessels, airways, and urinary tract, they are in constant contact with a wide variety of cells, putting high demands on the communication skills of these cells. The purinergic signaling system offers a dynamic and versatile way for local and rapid intercellular communication and involves three processes: nucleotide release, enzymatic degradation, and activation of purinergic receptors. With an impressive number of molecular members of the system (15 P2 receptor subtypes and in total 16 nucleotide-degrading enzymes), cells have managed to put purines and pyrimidines as well as their derivatives to use in an array of different areas, including regulation of flow, secretion, and vascular tone. Indeed, the purinergic signaling system is an ancient way of intercellular communication that most likely could be found in the first most primitive life form [1]. The scope of this review is to give an overview of exciting features of purinergic signaling and examples of gaps to fill in understanding its role in the cells lining the body-the endothelium and the epithelium. Purinergic signaling-an overviewExtracellular nucleotides exert their paracrine signaling by binding to P2 receptors present at the cell surface. The P2 receptor family is divided into two groups: P2X receptors, which are ligand-activated ion channels, and P2Y receptors, which are G protein-coupled receptors (reviewed in [2]). Each receptor is characterized by its affinity pattern for different nucleotides and different cell types display varying receptor profiles. While P2X receptors respond only to ATP, P2Y receptors can be activated by other nucleotides such as ADP, UTP, and UDP. Extracellular nucleotide concentrations are precisely regulated by ecto-enzymes, which cleave nucleotide tri-/diphosphates. The result of signaling by the extracellular nucleotides ATP/ADP, UTP/UDP and the nucleoside adenosine is both acute, for example the rapid platelet aggregation induced by ADP, and chronic, via changes in gene expression induced by P2 receptor stimulation. Ligand availability for P2 receptors is regulated by a group of enzymes termed ectonucleotidases. NTPDase1 (apyrase; CD39) cleaves ATP to AMP, NTPDase2 (CD39L1) cleaves ATP to ADP, and 5′-ectonucleotidase (CD73) generates adenosine from AMP. Adenosine is the end product of purinergic signaling, acting on adenosine receptors (A1, A2a, A2b, and A3; also termed P1 receptors) or recycling by the cell after reuptake through the equilibrating nucleoside transporters ENT1 and 2. UTP is believed to be released simultaneously with ATP via the same mechanism but at a lower concentration (UTP/ATP, 1:10-100). UTP is degraded in the same way as ATP, but the biological function of uridine is poorly understood and no uridine receptor has been identified. Figure 1 shows an outline of nucleotide metabolism. Purinergic toneAll investigators that have tried t...