It is becoming increasingly clear that the extracellular nucleotides ATP, ADP, UTP and UDP can affect solute and water transport in a variety of epithelia, including the nephron. Their actions are mediated by P2 receptors, broadly divided into two types: metabotropic P2Y receptors (mammalian sub-types 1, 2, 4, 6 and 11-14) and ionotropic P2X receptors (mammalian sub-types 1-7). Various P2 receptor sub-types are present in the kidney, both in the vasculature (see previous presentation) and in the tubular epithelium. Until recently, attempts to identify the P2 receptor sub-types in native renal epithelium relied largely on measurements of altered intracellular Ca²⁺ concentration in response to application of selected nucleotides, or on determination of mRNA expression (e.g., Bailey et al. 2000). The former approach suffers from poor specificity of P2 agonists and from uncertainty as to whether intracellular Ca²⁺ transients are a useful index of physiological function (Lehrmann et al. 2002); while the latter does not guarantee the presence of receptor protein. Using immunohistochemical techniques and available polyclonal antibodies, our laboratory has recently identified a number of P2 receptor sub-types along the rat nephron (Turner et al. 2003). P2Y₁ and P2Y₄ receptors were found in proximal tubule, and P2Y₂ receptors in both thin and thick ascending limb of Henle, as well as intercalated cells of medullary collecting duct. Low-level expression of P2X₄ and P2X₆ receptors was seen throughout the nephron, while P2X₅ receptors were present in the S3 segment of the proximal tubule and (usually) the collecting duct. Our knowledge of the functional consequences of stimulation of these receptors in native tissue is incomplete. A recent study has shown that stimulation of apical P2Y₁ receptors in rat proximal tubule can inhibit bicarbonate reabsorption (Bailey, 2004), but no information is yet available concerning the functional response (other than Ca²⁺ transients) to P2 receptor stimulation in the loop of Henle or distal tubule. Most attention has focussed on the collecting duct. It has been known for some time that basolateral P2 receptor stimulation inhibits vasopressin-stimulated water reabsorption in collecting ducts. More recently, it has been shown that stimulation of apical P2 receptors in collecting ducts inhibits K⁺ channels and ENaC-mediated sodium reabsorption (Unwin et al. 2003). However, the receptor sub-types responsible for these effects have not been firmly established: pharmacological profiling suggests that inhibition of sodium reabsorption in mouse collecting duct in vitro is mediated by P2Y₂ receptors (Lehrmann et al. 2002), whereas our own in vitro studies in the rat point towards a P2X-mediated effect, possibly a P2X_4/6 heteromer. Both P2Y and P2X receptors have also been shown to influence cell proliferation and differentiation, as well as cell death by necrosis and apoptosis. These effects might be important in some pathological conditions such as polycystic kidney disease, in which ‘trapped’ ATP could promote cyst development and expansion by stimulating cell proliferation and fluid secretion; and in some forms of renal inflammation, in which ATP released as a result of vascular injury and thrombosis may itself cause further cell injury and loss, as well as release of pro-inflammatory cytokines. Finally, it should be emphasized that, despite the physiological and pathological possibilities outlined above, we have only limited direct evidence for a regulatory role of this receptor system in the kidney. However, in our view this almost certainly reflects the complexity of the system, as well as our currently limited means of investigating it.