, 2005). Moreover, recent work has shown that the purinergic component of the respiratory drive is at most 30%, a fraction that relies on hemichannel-mediated Ulixertinib cost ATP release and that the actions of endogenous ATP on RTN neurons were not mediated by P2Y1 receptors, leaving open the intriguing possibility P2X receptors play a critical role (Wenker et al., 2012). Furthermore, in newborn rats, RTN

chemoreception depends only on the intrinsic chemosensitivity of neurons (Onimaru et al., 2012). In summary, the available data indicate that a component of central chemoreception is mediated by astrocyte ATP that likely acts on P2X receptors in the RTN, demonstrating how ATP neuromodulation has profound effects on RTN neuron function with clear behavioral outcomes in the form of respiratory responses to hypercapnia. Afferent nerves that carry information into the central nervous system can be excited at their peripheral ends either by direct mechanical distortion or by transmitters released from specialized sensory cells. Considerable evidence now supports the view that the transmitter released at some such sensory “first synapses” is ATP, and that it activates P2X receptors on the primary Palbociclib afferent nerve endings. Taste and Chemosensation. In response

to gustatory stimulation, Type II taste buds release ATP that acts on P2X2/3 heteromeric receptors to excite primary afferent nerves that run to the CNS in the facial or glossopharyngeal nerves ( Finger et al., 2005). Indeed, the release of ATP is itself driven in part by positive feedback through P2X2 receptors on the taste buds themselves ( Huang et al., 2011). A similar situation pertains with respect to sensory cells of the carotid body. In this case the glomus cells sense arterial oxygen levels. In response to hypoxia they release

ATP, and this acts on P2X receptors Resminostat to initiate impulses in the carotid sinus nerve ( Rong et al., 2003). Cough. Pulmonary vagal afferents can be directly excited by activation of P2X2/3 receptors ( Kwong et al., 2008), and P2X3 receptor antagonists reduce cough in a commonly used guinea pig model ( Kamei et al., 2005). ATP inhalation in humans induces cough and dyspnea, likely by direct activation of P2X receptors ( Basoglu et al., 2005). There are now available highly selective antagonists for receptors containing P2X3 subunits ( Gever et al., 2010) that may prove to have clinical utility. Urinary Bladder and Intestine. As the bladder becomes distended, the stretch in its wall can lead to ATP release from urothelial cells ( Ferguson et al., 1997). This excites the terminals of afferent fibers expressing heteromeric P2X2/3 receptors ( Zhong et al., 2003), and mice with a disrupted P2X3 receptor gene exhibit bladder hyporeflexia ( Cockayne et al., 2000).