Modulation of voltage‐ and ligand‐gated ion channels by neuronal P2Y receptors

Abstract

The present review summarizes data about the properties, distribution, and effects of neuronal P2Y receptors. Extracellular nucleotide receptors can be classified into two types belonging either to the P2X (ligand-gated cationic channels) or the P2Y type (G protein-coupled receptors). Neuronal P2Y receptors comprise five cloned and functionally defined classes of which P2Y 1 , P2Y 6 , P2Y 11 , P2Y 12 , and P2Y 13 occur in the central nervous system. Various types of P2Y receptors stimulate inwardly rectifying potassium channels, positively or negatively modulate the high-voltage activated Ca 2+ current and increase the intracellular free Ca 2+ concentration in neuronal preparations. Moreover, in a subpopulation of pyramidal cells of the rat prefrontal cortex (PFC), the P2Y 2 receptor potentiates the function of a ligand-gated cationic channel, the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. This effect is G protein-mediated and utilizes the phospholipase C/inositol 1,4,5-trisphosphate/ Ca 2+ /calmodulin kinase II pathway. It appears that P2Y 2 receptors situated at astrocytes release glutamate, which in turn modulates NMDA receptors of neighbouring neurons via stimulation of group I metabotropic glutamate receptors. In contrast, P2Y 1 receptors inhibit the conductance of NMDA receptor-channels in all PFC pyramidal cells investigated. This effect is fast in onset and does not depend on G protein activation. It is suggested that P2Y 1 receptors alter the function of NMDA receptors by a direct protein-protein coupling in the membrane. Because ATP and dopamine are supposed to be coreleased from dopaminergic fibers onto layer V pyramidal cells, both neurotransmitters may interact with the neuronal NMDA receptor. Hence, D 1 dopamine receptors and P2Y 1 /P2Y 2 receptors may be involved in the fine tuning of higher order cognitive functions including learning and memory. Drug Dev. Res. 59:49-55, 2003.

Pathophysiology and Therapeutic Potential of Purinergic Signaling

“…Clearly there are multiple roles for P2 and P1 receptors in relation to learning and memory, but the way that therapeutic manipulation of purinergic mechanisms can be used to improve these functions is still unresolved. Higher order cognitive functions, including learning and memory in the prefrontal cortex appear to involve P2Y receptor signaling (Wirkner et al, 2003).…”