Purinergic regulation of the epithelial Na⁺ channel

Abstract

Summary The epithelial Na+ channel (ENaC) is a major conductive pathway that transports Na + across the apical membrane of the distal nephron, the respiratory tract, the distal colon and the ducts of exocrine glands. ENaC is regulated by hormonal and humoral factors, among which are extracellular nucleotides that can be available from the epithelial cells themselves.2. Extracellular nucleotides, via the P2Y 2 receptors (P2Y 2 Rs) at the basolateral and apical membrane of epithelia, trigger signalling systems that cause inhibition of the activity of ENaC and activation of Ca 2+ -dependent Cl − secretion.3. Recent data from our laboratory suggest that stimulation of the P2Y 2 Rs at the basolateral membrane inhibits activity of ENaC by a signalling mechanism that involves Gβγ subunits freed from a PTX-sensitive G protein and phospholipase C-β4. A similar signalling mechanism is also partially responsible for inhibition of ENaC during activation of apical P2Y 2 Rs 4. Stimulation of apical P2Y 2 Rs also stimulates an additional signalling mechanism that inhibits ENaC, involving the activated Gα subunit of a PTX-insensitive G protein, and activation of an unidentified PLC. The effect of this PTX-insensitive system requires the activity of the basolateral Na + /K + /2Cl − co-transporter.

Influence of Exercise on Airway Epithelia in Cystic Fibrosis

“…P2X activation increases Ca^^ flux via the opening of ATP-dependent Ca^ĉ hannels (91). Therefore, purinergic activation stimulates Caactivated chloride channels via elevated intracellular Ca^â nd reciprocally inhibits ENaC Na^ absorption via PIP2 hydrolysis to increase ASL (41,42,60). Cilia beat frequency is regulated by both P2Y and P2X receptors (88).…”

The touching story of purinergic signaling in epithelial and endothelial cells

“…The way that P2Y2 receptor activation influences ENaC activity has previously been attributed to PLC activation and PIP2 depletion [43]. Recently, a role for increased intracellular Cl − concentration via the basolateral Na + K + 2Cl − cotransporter has been suggested in the P2Y2-dependent regulation of ENaC activity [44]. This pathway is only accessible for apically located P2Y2 receptors, while basolateral activation has considerably smaller effect size and involves a different signaling mechanism that also can be employed by apical receptors [44].…”

“…Recently, a role for increased intracellular Cl − concentration via the basolateral Na + K + 2Cl − cotransporter has been suggested in the P2Y2-dependent regulation of ENaC activity [44]. This pathway is only accessible for apically located P2Y2 receptors, while basolateral activation has considerably smaller effect size and involves a different signaling mechanism that also can be employed by apical receptors [44]. There are studies from several epithelial tissues describing increased activation of the ENaC after P2Y receptor stimulation, but this is thought to be due to indirect effects of the purinergic degradation product adenosine and effects on other ion channels [27].…”

Regulation of Epithelial Sodium Transport via Epithelial Na+ Channel

“…Two types of amiloride-sensitive Na + -permeable channels have been reported in rat fetal alveolar type II epithelial cells [19, 22, 73, 74]. Both types of amiloride-sensitive channels are activated by cytosolic Ca 2+ [19, 22, 73, 74] unlike other types of amiloride-sensitive channels (ENaCs), which are inhibited by cytosolic Ca 2+ via a PKC-dependent pathway [77–79]. It has been reported that beta-agonist stimulates the fluid clearance from alveolar space [69].…”