FIGURE 5.

Nucleotide/P2 receptor system and tubuloglomerular feedback. Numbers in circles refer to the following sequence of events: 1) increase in concentration-dependent uptake of Na⁺, K⁺, and Cl⁻ via the furosemide-sensitive Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) in macula densa cells; 2) basolateral release of ATP; 3 and 4) transport-dependent, intra- and/or extracellular generation of adenosine (ADO); 5 and 6) the extracellular generation involves local ecto-NTPDase1 (CD39) and ecto-5′-nucleotidase (CD73); 7) extracellular ADO activates adenosine A₁ receptors triggering an increase in cytosolic Ca²⁺ on extraglomerular mesangium cells (MC; not shown) and smooth muscle cells of the afferent arteriole (VSMC) resulting in afferent arteriolar vasoconstriction; 8) extracellular ATP activates P2 receptors on extraglomerular MC and increases cytosolic Ca²⁺; the intensive coupling between extraglomerular MC, intraglomerular MC (not shown), and VSMC of the afferent arteriole by gap junctions contributes to the propagation of the Ca²⁺ signal; 9 and 10) ATP release and P2 receptor activation also contribute to the cell to cell propagation of the Ca²⁺ signal, including to VSMC where activation of P2X1 receptors causes afferent arteriolar vasoconstriction; 11) extracellular ATP may also activate P2Y₂ receptors on the basolateral membrane of macula densa cells with unknown function. See text for further explanations. [Modified from Vallon et al. (525).]