Consistent with this suggestion, electron microscopy shows that P2X2 and P2X4 receptors are generally not located in synapses at BMS-754807 molecular weight sites directly opposite neurotransmitter release

from the presynaptic terminal (Figure 5), residing instead at the edges of the postsynaptic density (Rubio and Soto, 2001). Recent single molecule imaging and tracking experiments in cell culture support these findings and show that P2X2 receptors do not enter fast glutamatergic synapses even when heterologously overexpressed and strongly activated by ATP (Richler et al., 2011). These data offer an explanation for the rarity of fast ATP neurotransmission in the brain and also raise important cell biological

questions about why P2X receptors are excluded from synapses. In general, activation of presynaptic P2X receptors increases neurotransmitter release probability due to influx of calcium (Figure 5), although depression of action potential evoked neurotransmitter release can also occur as a result of action potential failure and/or shunting in axons (Engelman and MacDermott, 2004; Khakh and Henderson, 2000). Presynaptic P2X receptors may be activated by endogenous ATP release in some synapses. Although, presynaptic P2X responses have now been described in many parts of the brain, we lack a these satisfactory understanding JAK cancer of the precise physiological function of this form of presynaptic facilitation. A presynaptic action of ATP forms one aspect of its overall effect in the hippocampus, within the feed-forward circuit formed between CA3 pyramidal neurons, GABAergic interneurons and output CA1 pyramidal neurons. Progress from several groups is beginning to converge and suggest ways in

which ATP signaling may be involved in the integrative actions of this circuit. Presynaptic P2X2 receptors increase glutamate release onto interneurons but not pyramidal neurons (Khakh et al., 2003), whereas postsynaptic P2Y1 receptors depolarize interneurons (Bowser and Khakh, 2004; Kawamura et al., 2004). However, most likely because there are few pre- or postsynaptic ATP receptors that depolarize CA1 pyramidal neurons directly (Baxter et al., 2011; Khakh et al., 2003), the net effect on output neurons is dominated by heightened GABAergic synaptic inhibition. Thus, in the stratum radiatum region of the hippocampus, the cellular effects of ATP are excitatory, but the overall result on the network is dominated by increased inhibition, implying that ATP acts as a “physiological brake” to excitation within this feed-forward circuit (Bowser and Khakh, 2004).