Calcium-activated nonselective (CAN) cation channels are expressed in various excitable and nonexcitable cells supporting important cellular responses such as neuronal bursting activity, fluid secretion, and cardiac rhythmicity. We have cloned and characterized a second form of TRPM4, TRPM4b, a member of the TRP channel family, as a molecular candidate of a CAN channel. TRPM4b encodes a cation channel of 25 pS unitary conductance that is directly activated by [Ca²⁺]i with an apparent K_D of ∼400 nM. It conducts monovalent cations such as Na⁺ and K⁺ without significant permeation of Ca²⁺. TRPM4b is activated following receptor-mediated Ca²⁺ mobilization, representing a regulatory mechanism that controls the magnitude of Ca²⁺ influx by modulating the membrane potential and, with it, the driving force for Ca²⁺ entry through other Ca²⁺-permeable pathways.