, 2000). This study also showed that the functional interactions occurred in synaptically coupled myenteric neurons where nicotinic fast excitatory postsynaptic currents were occluded during activation of endogenously coexpressed Lonafarnib price P2X channels. Similar experiments have now been repeated with several ion channel combinations showing that cross-inhibition between P2X receptors and members of the nicotinic receptor-like family are common ( Barajas-López et al., 1998, 2002; Boué-Grabot et al., 2003, 2004a, 2004b).

Most recently, functional interactions have been reported for P2X receptors and acid sensing ion channels (ASIC) ( Birdsong et al., 2010) as well as between P2X3 receptors and TRPV1 channels ( Stanchev et al., 2009). We comment here on general themes that emerge. Overall, the data suggest P2X receptors form molecular scale partnerships with distinct ion channels. Fluorescence resonance energy transfer (FRET) experiments show close interactions between P2X2 and α4β2 nicotinic, P2X5 and ASIC, as well as P2X2 and GABAA receptors, which provides a basis for functional interactions within

the plasma membrane (Birdsong et al., 2010; Khakh et al., 2005; Shrivastava et al., 2011). Cross-inhibition between P2X receptors and nicotinic channels can occur in the absence of ion flow through P2X2 during a closed-desensitized Apoptosis Compound Library cost state and is likely due to conformational coupling (Khakh et al., 2000). Similarly, the interaction between P2X5 and ASIC channels is independent of ion flow through P2X5 receptors (Birdsong et al., 2010). In the case of spinal neurons, activation of P2X2 receptors increases the lateral mobility of GABAA receptors, adding a previously unknown facet to the interactions between these receptor types (Shrivastava et al., 2011). An important question for future exploration is to determine if cross-inhibition has behavioral

consequences, either physiologically or during disease states, and it will also be important to nail down the molecular basis for the interactions. P2X receptors are regulated in a use-dependent manner and it is likely these mechanisms contribute in important ways to their neuromodulatory (-)-p-Bromotetramisole Oxalate responses in the brain. To date, two mechanisms have emerged: regulation of trafficking and regulation by Ca2+ sensors. P2X4 receptors display several types of dynamic trafficking including endocytosis, lysosomal secretion and lateral mobility. A robust observation has been the role of trafficking of P2X4 receptors through dynamin-dependent endocytosis, and P2X4 receptors undergo constitutive and regulated endocytosis mediated by a novel noncanonical endocytic motif (YXXGL) (Bobanovic et al., 2002; Royle et al., 2002, 2005).