Slick (Slo2.1) and Slack (Slo2.2) are two novel members of the mammalian Slo potassium channel gene family that may contribute to the resting potentials of cells and control their basal level of excitability. Slo2 channels have sensors that couple channel activity to the intracellular concentrations of Na+ and Cl- ions (Yuan et al., 2003). We now report that activity of both Slo2 channels is controlled by neuromodulators through Galphaq-protein coupled receptors (GqPCRs) (the M1 muscarinic receptor and the mGluR1 metabotropic glutamate receptor). Experiments coexpressing channels and receptors in Xenopus oocytes show that Slo2.1 and Slo2.2 channels are modulated in opposite ways: Slo2.1 is strongly inhibited, whereas Slo2.2 currents are strongly activated through GqPCR stimulation. Differential regulation involves protein kinase C (PKC); application of the PKC activator PMA, to cells expressing channels but not receptors, inhibits Slo2.1 whole-cell currents and increases Slo2.2 currents. Synthesis of a chimera showed that the distal carboxyl region of Slo2.1 controls the sensitivity of Slo2.1 to PMA. Slo2 channels have widespread expression in brain (Bhattacharjee et al., 2002, 2005). Using immunocytochemical techniques, we show coexpression of Slo2 channels with the GqPCRs in cortical and hippocampal brain sections and in cultured hippocampal neurons. The differential control of these novel channels by neurotransmitters may elicit long-lasting increases or decreases in neuronal excitability and, because of their widespread distribution, may provide a mechanism to activate or repress electrical activity in many systems of the brain.