Programme Contents

Purinergic regulation of epithelial Na⁺ channels

The epithelial Na⁺ channels (ENaC) expressed in Na⁺-absorbing tissues, such as the kidney collecting duct, distal colon and the respiratory epithelium, play an important role in Na⁺ and fluid homeostasis, controlling blood pressure and regulating the level of alveolar fluid. Aberrations of ENaC function may lead to hypertension, hypotension, pulmonary edema and reduction of mucociliary clearance of the airways. The epithelia lining the lung, kidney and gut release nucleotides in response to physiological stimuli, activating P2Y purinergic receptors in either an autocrine or paracrine manner to regulate an array of physiological mechanisms, including ion transport by these tissues. In the aldosterone-sensitive segment of the kidney, activation of purinergic receptors at the apical or basolateral membranes significantly inhibits amiloride-sensitive Na⁺ absorption mediated by the epithelial Na⁺ channels (Vallon, 2008). Similarly, inhibition of ENaC during purinergic receptor activation has been reported in epithelia lining the lung and gut (Kunzelmann et al., 2001; Matos et al., 2007). The absence of any negative effect of nucleotides on the activity of ENaC in P2Y₂ knock-out mice (Matos et al., 2007) suggests that P2Y₂ receptors may be responsible for purinergic regulation of ENaC. In the past decade, the P2Y₂ receptor-activated signaling mechanisms that regulate activity of ENaC have been extensively investigated. It has been reported that nucleotides may mediate their effect on ENaC via pertussis toxin-sensitive G-proteins (Kunzelmann et al., 2002). Our recent studies, which used gene interference and gene expression techniques, suggest that free Gβγ-dimers, released from pertussis-sensitive G-proteins during P2Y₂ receptor activation, may mediate the purinergic regulation of ENaC activity. The signaling mechanism involved requires activity of PLCβ4, but appears to be independent of the traditional signaling effector molecules downstream of PLC, such as [Ca²⁺]_i , PKC or MAP kinase. We conclude that depletion of membrane phophatydylinositol 4,5-biphosphate (PIP₂), induced by activity of PLC activated during P2Y₂ receptor stimulation, may play an important role in mediating downregulation of ENaC activity during P2Y₂ receptor activation.

Kunzelmann K, Schreiber R, Boucherot A. (2001) Kidney International, 60: 455-61.

Kunzelmann K, Schreiber R, Cook D. (2002) Pflügers Archive European Journal of Physiology, 444: 220-6.

Ma HP, Chou CF, Wei SP. Eaton DC. (2007) Pflügers Archive European Journal of Physiology, 455: 169-180.

Matos JE, Sorensen MV, Geyti CS, Robaye B, Boeynaems JM, Leipziger J. (2007) Pflügers Archive European Journal of Physiology, 454: 977-87.

Vallon V. (2008) American Journal of Physiology, 94: F10-27.