Abstract
ATP is the dominant messenger for astrocyte‐to‐astrocyte calcium‐mediated communication. Definition of the exact ATP/P2 receptors in astrocytes and of their coupling to intracellular calcium ([Ca^2+^]~i~) has important implications for brain physiology and pathology. We show that, with the only exception of the P2X~6~ receptor, primary rat cortical astrocytes express all cloned ligand‐gated P2X (i.e., P2X~1–5~ and P2X~7~) and G‐protein‐coupled P2Y receptors (i.e., P2Y~1~, P2Y~2~, P2Y~4~, P2Y~6~, and P2Y~12~). These cells also express the P2Y‐like UDP‐glucose receptor, which has been recently recognized as the P2Y~14~ receptor. Single‐cell image analysis showed that only some of these receptors are coupled to [Ca^2+^]~i~. While ATP induced rapid and transient [Ca^2+^]~i~ increases (counteracted by the P2 antagonists suramin, pyridoxal‐phosphate‐6‐azophenyl‐2′‐4′‐disulfonic acid and oxidized ATP), the P2X~1~/P2X~3~ agonist αβmeATP produced no changes. Conversely, the P2X~7~ agonist BzATP markedly increased [Ca^2+^]~i~; the presence and function of the P2X~7~ receptor was also confirmed by the formation of the P2X~7~ pore. ADP and 2meSADP also produced [Ca^2+^]~i~ increases antagonized by the P2Y~1~ antagonist MRS2179. Some cells also responded to UTP but not to UDP. Significant responses to sugar‐nucleotides were also detected, which represents the first functional response reported for the putative P2Y~14~ receptor in a native system. Based on agonist preference of known P2 receptors, we conclude that, in rat astrocytes, ATP‐induced calcium rises are at least mediated by P2X~7~ and P2Y~1~ receptors; additional receptors (i.e., P2X~2~, P2X~4~, P2X~5~, P2Y~2~, P2Y~4~, and P2Y~14~) may also contribute. © 2003 Wiley‐Liss, Inc.