The TASK family (TASK1 and TASK3) of two pore domain potassium (K2P) channels underlie leak K currents in a number of different CNS neurons. These channels are regulated by a variety of physiological mediators such as changes in extracellular pH and activation of G protein coupled receptors and by a number of pharmacological agents such as volatile anesthetic agents, ruthenium red, zinc ions and methanandamide (see Kim 2005, Mathie 2007). Using whole-cell electrophysiological recordings of currents through TASK channels expressed in tsA 201 cells, we have found that human TASK1 and TASK3 channels are both sensitive to block by (R)-methanandamide (a stable analogue of the endogenous cannabinoid anandamide), despite this compound once being regarded as a relatively selective TASK1 inhibitor (Maingret et al 2001). Methanandamide (3 μM) produced inhibitions of 81 ± 2% (n = 11, mean ± SEM) and 64 ± 4% (n = 8) for TASK3 and TASK1 channels, respectively. For either TASK1 or TASK3, block by methanandamide was virtually irreversible, unless cells were washed with BSA (1 mg/ml). Previously, G protein-mediated inhibition and volatile anesthetic-mediated enhancement of TASK1 and TASK3 channels has been shown to require the presence of six amino acids (VLRFLT for TASK3) at the interface between the final transmembrane domain and the cytoplasmic C terminus (Talley & Bayliss 2002). We have confirmed these observations for TASK3 channels with a construct where these six amino acids have been deleted. Currents through channels in this deletion mutant were significantly (p < 0.05, Student’s t-test) reduced in amplitude from 67 ± 9 pA/pF (n = 18) to 26 ± 2 pA/pF (n = 29), when measured as the difference current between -40 mV and -80 mV. These channels were no longer inhibited by activation of muscarinic receptors (0.1 μM muscarine producing 6 ± 2 % inhibition, n = 3) nor by co-transfection of cells with constitutively active Gαq (24 ± 3 pA/pF, n = 13). The mutant channels were, however, inhibited as normal by zinc (Clarke et al 2004) with 100 μM giving 88 ± 5 % inhibition (n = 5). Methanandamide no longer inhibited and, instead, now slightly enhanced current through this VLRFLT deletion mutant (13 ± 4 % (n = 9) enhancement by 3 μM methanandamide). Thus methanandamide converges on the same intracellular gating pathway as G protein-mediated inhibition and volatile anesthetic-mediated enhancement of TASK3 channels. It remains to be determined, however, whether this region in TASK channels is involved in the gating of the channel per se, the binding of modulatory molecules, or in the transduction of the signal to the gate following binding.