K_Ca4.1 (Na⁺-activated K⁺ channel, Slack, Slo2.2, KCNT1) is a member of a subgroup within the Ca²⁺ activated K⁺ channel family. The Slack (Sequence like a Ca²⁺-activated K⁺ channel) and Slick (Sequence like an intermediate conductance K⁺ channel, KCNT2) genes, which encode Na⁺-activated K⁺ (K_Na) channels, are expressed at high levels in neurons in several areas of the nervous system¹.

Although K_Ca4.1 is functionally a Na⁺-activated K⁺ channel, it is termed K_Ca by the IUPHAR nomenclature, due to its sequence homology to other K_Ca channels.

The family’s protein topology consists of six transmembrane domains that flank a single and highly conserved pore region with intracellular N- and C-termini. As is the case for the voltage-dependent K⁺ channels, the functional unit for K_Ca4.1 channels is composed of four subunits that can assemble as either homo- or heteromers with KCNT2 (Slick). K_Ca4.1 and Slick subunits coassemble to form heteromeric channels that differ from the homomers in their unitary conductance, kinetic behavior, subcellular localization, and response to activation of protein kinase C. Heteromer formation requires the N-terminal domain of Slack-B, one of the alternative splice variants of the K_Ca4.1 channel. This cytoplasmic N-terminal domain of Slack-B also facilitates the localization of heteromeric K_Na channels to the plasma membrane².

K⁺ channels sensitive to intracellular Na⁺, termed K_Na channels, shape neuronal excitability. K_Na channels contribute to the adaptation of firing rates and to slow after-hyperpolarizations that follow repetitive firing. In certain neurons, they also appear to be activated by Na⁺ influx accompanying single action potentials. Their molecular properties also suggest that these channels contribute to the response of neurons to hypoxia¹. K_Ca4.1 channels were shown to be expressed also in dorsal root ganglion (DRG) neurons, where these channels were found to contain a NAD⁺ binding sequence and to be modulated by this endogenous compound³.