In human T lymphocytes patch-clamp experiments have revealed the expression of two major subtypes of SK channels. In excitable cells these channel types play significant roles in shaping excitablility as well as firing patterns especially since their open probability is regulated by the intracellular second messenger Ca2+. In nonexcitable T cells, SK channels could hyperpolarize the membrane during the rise in [Ca2+]i elicited via T-cell receptor stimulation. This hyperpolarization in turn could contribute to enhanced Ca2+ entry by increasing the driving force for Ca2+ to enter the cell [see also Verheugen, this issue] via Icrac· This scenario plays an increasingly significant role in already activated T cells due to the up-regulated number of SK channels in activated human peripheral T lymphocytes. We have used whole-cell recording to determine the electrophysiological properties of current through SKAPA channels in Jurkat T cells and through SKctx channels in activated HPB T lymphocytes. The main similarities between the two channel types are their Ca2+ sensitivity and voltage dependence. The SK channel activity depends steeply on [Ca2+]i, suggesting that multiple Ca2+ must bind to the channel or an associated molecule in order to open the pore. The Ca2+ concentration at which half the channels are activated is Ì° 400-450 nM and the activity of both channel types is voltage-independent. The major difference between the two channel types is their pharmacology regarding peptide toxins like apamin, scyllatoxin, charybdotoxin, as well as other blockers like TEA+. SKcTX and SKapa channels show minor differences in Ba2+ sensitivity, induction time course, selectivity, and single-channel conductance. All these properties together should allow a better distinction between these two different types of SK channels in lymphocytes with the ultimate goal to identify the genes encoding these channels.