The gene for hSK4, a novel human small conductance calcium-activated potassium channel, or SK channel, has been identified and expressed in Chinese hamster ovary cells. In physiological saline hSK4 generates a conductance of approximately 12 pS, a value in close agreement with that of other cloned SK channels. Like other members of this family, the polypeptide encoded by hSK4 contains a previously unnoted leucine zipper-like domain in its C terminus of unknown function. hSK4 appears unique, however, in its very high affinity for Ca 2؉ (EC 50 of 95 nM) and its predominant expression in nonexcitable tissues of adult animals. Together with the relatively low homology of hSK4 to other SK channel polypeptides (approximately 40% identical), these data suggest that hSK4 belongs to a novel subfamily of SK channels.In mammals, small conductance calcium-activated potassium channels, or SK channels, are thought to underlie currents that have been described in a wide range of tissues, including brain (1-13), peripheral nervous system (14-16), skeletal muscle (17-19), adrenal chromaffin cells (20)(21)(22), leukocytes (23-28), erythrocytes (29-32), colon (33, 34), and airway epithelia (35,36). Pharmacologically, certain types of SK channels have been distinguished by their sensitivities to the bee venom apamin (5, 7-23, 37), whereas other functionally related conductances appear insensitive (7,24,27,34). Features that distinguish members of this family from their closest phenotypic neighbors, the maxi-K calcium-activated, or BK, potassium channels, are the SK channels' low conductance (less than 50 pS), the weak or negligible dependence of their activity on membrane voltage, and their high affinity for Ca 2ϩ (EC 50 Ͻ 1 M) (3, 19-23, 25, 26, 33-40).Fragments of SK genes first were identified in computerbased searches of GenBank's database of expressed sequence tags (ESTs) for cDNAs encoding sequences resembling the pore domains of known families of K ϩ channels (41). We have extended this work by identifying ESTs including the gene encoding human SK4 (hSK4), a member of a novel subfamily of SK channels, and expressing one of these cDNAs in Chinese hamster ovary cells. In addition, we cloned the full-length gene of rSK1 (41).Members of the first subfamily to be described are predominantly expressed in excitable tissues and are half-maximally activated at cytosolic free Ca 2ϩ concentrations in the range of 600-700 nM (41). The hSK4 channel differs from these in that its transcript is found in nonexcitable tissues and is halfactivated at 95 nM free Ca 2ϩ , indicating it is likely to be open at resting levels of Ca 2ϩ in certain types of cells. The hyperpolarization resulting from the activity of hSK4 suggests that this channel could regulate electrogenic transport. METHODSCloning of SK Genes. The two P regions of the yeast TOK channel were used to screen the EST database of GenBank using the BLAST algorithm (42). One of the ESTs that was identified as a novel potential mammalian K ϩ channel cDNA was labeled by random prim...
Large-conductance calcium-activated potassium channels (maxi-K channels) have an essential role in the control of excitability and secretion. Only one gene Slo is known to encode maxi-K channels, which are sensitive to both membrane potential and intracellular calcium. We have isolated a potassium channel gene called Slack that is abundantly expressed in the nervous system. Slack channels rectify outwardly with a unitary conductance of about 25-65 pS and are inhibited by intracellular calcium. However, when Slack is co-expressed with Slo, channels with pharmacological properties and single-channel conductances that do not match either Slack or Slo are formed. The Slack/Slo channels have intermediate conductances of about 60-180 pS and are activated by cytoplasmic calcium. Our findings indicate that some intermediate-conductance channels in the nervous system may result from an interaction between Slack and Slo channel subunits.
Although dendritic cell (DC) dysfunction in cancer is a well-recognized consequence of cancer-associated inflammation that contributes to immune evasion, the mechanisms that drive this process remain elusive. Here, we show the critical importance of tumor-derived TLR2 ligands in the generation of immunosuppressive IL-10-producing human and mouse DCs. TLR2 ligation induced two parallel synergistic processes that converged to activate STAT3: stimulation of autocrine IL-6 and IL-10 and upregulation of their respective cell surface receptors, which lowered the STAT3 activation threshold. We identified versican as a soluble tumor-derived factor that activates TLR2 in DCs. TLR2 blockade in vivo improved intra-tumor DC immunogenicity and enhanced the efficacy of immunotherapy. Our findings provide a basis for understanding the molecular mechanisms of DC dysfunction in cancer and identify TLR2 as a relevant therapeutic target to improve cancer immunotherapy.
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