Koizumi et al., (2004) demonstrated the importance of ATP and P2Y₂ receptors in signalling between keratinocytes and sensory neurones. A population of neurones innervating the epidermis are selectively sensitive to ATP in mice (Dussor et al., 2008). They also express mas-related G protein-coupled receptor D (MrgprD), activation of which inhibits the M-current in IB₄-labelled rat dorsal root ganglion (DRG) neurones (Dussor et al., 2008; Crozier et al., 2007). The P2Y₂ agonist, uridine triphosphate (UTP), has long been known to inhibit the M-current in bullfrog sympathetic neurones (Adams et al., 1982). Previously we reported that “non-peptidergic” DRG neurones from a mouse that expressed green fluorescent protein (GFP) in epidermal primary afferents fired in a predominantly transient manner (Bruce et al., 2008). We investigated whether this firing pattern was due to the presence of an M-current and, if so, how it was modulated by endogenous P2Y agonists. Transgenic mice carrying the thy1.2-egfp gene on a C57/Bl6 template (SA36 strain) were deeply anaesthetised with halothane and killed by decapitation. Dissociated DRG neurones were short-term cultured (1-3) days and used for whole-cell voltage or current clamp recording. The M-current was isolated in voltage-clamped DRG neurones (25-31 µm diameter) using an inactivation protocol and 1mM CsCl. XE-991 (10µM) and UTP (10µM) significantly reduced the conductance through K_v7 channels at -30 to -50 mV and -30 to -40 mV respectively (P<0.05, Dunnetts T). ADP (10µM) had no significant effect on M-current conductance. Under current clamp conditions, DRG neurones produced predominately transient responses to depolarising current injections (16/20 cells). UTP (10µM) increased afterdepolarisation amplitude and secondary spike frequency (3/5 cells). ADP (10µM) reduced or blocked the primary spike in some transiently firing neurones (2/5 cells). Bath applied ATP (10µM) elicited spontaneous activity (4/6 cells) and tonic firing in response to current injection (2/6 cells). This data demonstrates that the excitability of neurones anatomically positioned to receive input from keratinocytes can be modulated by nucleotides through P2Y/K_v7 signalling.