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Am J Physiol Renal Physiol 284: F419-F432, 2003; doi:10.1152/ajprenal.00075.2002
0363-6127/03 $5.00
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Vol. 284, Issue 3, F419-F432, March 2003

INVITED REVIEW
Control of epithelial transport via luminal P2 receptors

Jens Leipziger

Department of Physiology, The Water and Salt Research Center, Aarhus University, 8000 Aarhus C, Denmark

P2 membrane receptors are specifically activated by extracellular nucleotides like ATP, ADP, UTP, and UDP. P2 receptors are subdivided into metabotropic P2Y and ionotropic P2X receptors. They are expressed in all tissues and induce a variety of biological effects. In epithelia, they are found in both the basolateral and the luminal membranes. Their widespread luminal expression in nearly all transporting epithelia and their effect on transport are summarized. The P2Y2 receptor is a prominent luminal receptor in many epithelia. Other luminal P2 receptors include the P2X7, P2Y4, and P2Y6 receptors. Functionally, luminal P2Y2 receptor activation elicits differential effects on ion transport. In nearly all secretory epithelia, intracellular Ca2+ concentration-activated ion conductances are stimulated by luminal nucleotides to induce Cl-, K+, or HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> secretion. This encompasses respiratory and various gastrointestinal epithelia or tissues like the conjunctiva of the eye and the epithelium of sweat glands. In the distal nephron, all active transport processes appear to be inhibited by luminal nucleotides. P2Y2 receptors inhibit Ca2+ and Na+ absorption and K+ secretion. Commonly, in all steroid-sensitive epithelia (lung, distal nephron, and distal colon), luminal ATP/UTP inhibits epithelial Na+ channel-meditated Na+ absorption. ATP is readily released from epithelial cells onto their luminal aspect, where ecto-nucleotidases promote their metabolism. Adenosine generated by the action of 5'-nucleotidase may elicit further effects on ion transport, often opposite those of ATP. ATP release from epithelia continues to be poorly understood. Integrated functional concepts for luminal P2 receptors are suggested: 1) luminal P2 receptors are part of an epithelial "secretory" defense mechanism; 2) they may be involved in the regulation of cell volume when transcellular solute transport is out of balance; 3) ATP and adenosine may be important autocrine/paracrine regulators mediating cellular protection and regeneration after ischemic cell damage; and 4) ATP and adenosine have been suggested to mediate renal cyst growth and enlargement in polycystic kidney disease.

P2Y; P2X; chloride secretion; sodium absorption; epithelial sodium channel; potassium secretion


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