Ca2+-activated K+ efflux limits complement-mediated lysis of human erythrocytes.

Halperin, José A.; Brugnara, Carlo; Nicholson‐Weller, Anne

doi:10.1172/jci114039

Cited by 36 publications

(29 citation statements)

References 22 publications

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“…3B shows the percentage of red cell lysis from wild-type animals at the indicated relative solution tonicity in the absence (E) and presence (f) of 5 M A23187, which was used to increase intracellular Ca 2ϩ levels. As shown previously (11,27), activation of the K ϩ permeability (with consequent cell shrinkage) protects cells from hypotonic lysis. In the absence of A23187, 50% of the cells lysed when relative tonicity was reduced to 0.47.…”

Section: Resultssupporting

confidence: 73%

Physiological Roles of the Intermediate Conductance, Ca2+-activated Potassium Channel Kcnn4

Begenisich

Nakamoto

Ovitt

et al. 2004

Journal of Biological Chemistry

179

182

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Three broad classes of Ca2؉ -activated potassium channels are defined by their respective single channel conductances, i.e. the small, intermediate, and large conductance channels, often termed the SK, IK, and BK channels, respectively. SK channels are likely encoded by three genes, Kcnn1-3, whereas IK and most BK channels are most likely products of the Kcnn4 and Slo (Kcnma1) genes, respectively. IK channels are prominently expressed in cells of the hematopoietic system and in organs involved in salt and fluid transport, including the colon, lung, and salivary glands. IK channels likely underlie the K ؉ permeability in red blood cells that is associated with water loss, which is a contributing factor in the pathophysiology of sickle cell disease. IK channels are also involved in the activation of T lymphocytes. The fluid-secreting acinar cells of the parotid gland express both IK and BK channels, raising questions about their particular respective roles. To test the physiological roles of channels encoded by the Kcnn4 gene, we constructed a mouse deficient in its expression. Kcnn4 null mice were of normal appearance and fertility, their parotid acinar cells expressed no IK channels, and their red blood cells lost K ؉ permeability. The volume regulation of T lymphocytes and erythrocytes was severely impaired in Kcnn4 null mice but was normal in parotid acinar cells. Despite the loss of IK channels, activated fluid secretion from parotid glands was normal. These results confirm that IK channels in red blood cells, T lymphocytes, and parotid acinar cells are indeed encoded by the Kcnn4 gene. The role of these channels in water movement and the subsequent volume changes in red blood cells and T lymphocytes is also confirmed. Surprisingly, Kcnn4 channels appear to play no required role in fluid secretion and regulatory volume decrease in the parotid gland.It has become clear that multiple types of Ca 2ϩ -activated potassium channels underlie a wide range of distinct physiological processes. Physiological and pharmacological analyses have subdivided Ca 2ϩ -activated potassium channels into three groups, i.e. the small, intermediate, and large conductance channels, often termed SK, 1 IK, and BK channels, respectively. IK channels, as their designation implies, have a single channel conductance intermediate between the SK and BK channels. These three functional groups have rather distinct pharmacological profiles, and SK, IK, and BK channels can be specifically blocked by apamin, clotrimazole, and paxilline, respectively. SK and IK channels are encoded by four genes of the KCNN gene family. The three SK channels, KCNN1-3, share ϳ70 -75% amino acid identity. The IK channel KCNN4 is encoded by a protein sharing only ϳ40% amino acid identity with each of the three SK channels, KCNN1-3.

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Section: Resultssupporting

confidence: 73%

Physiological Roles of the Intermediate Conductance, Ca2+-activated Potassium Channel Kcnn4

Begenisich

Nakamoto

Ovitt

et al. 2004

Journal of Biological Chemistry

179

182

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“…Moreover, inhibition of mIK1 was not attenuated by the substitution of 3-iodotyrosine for tyrosine at residue 36 of ChTX (Fig. 4), a critical residue for inhibition of skeletal muscle 6 Among K ir channel mRNAs (data not shown), ROMK was undetectable after 38 cycles amplification, and IRK1 (36 cycles) steadily increased from very low levels at day 0 to low levels at days 10 -12. In contrast, mRNA levels of IRK2 (33 cycles) and IRK3 (36 cycles) steadily decreased during the observed periods.…”

Section: Effect Of the Ik1 Inhibitor Clt On Stem Cell Proliferationmentioning

confidence: 87%

“…In addition, no PCR products were amplified from reactions from which reverse transcriptase was omitted (data not shown). 6 …”

Section: Fig 8 Camentioning

confidence: 99%

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cDNA Cloning and Functional Characterization of the Mouse Ca2+-gated K+ Channel, mIK1

Vandorpe

Shmukler

Jiang

et al. 1998

Journal of Biological Chemistry

189

107

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We have cloned from murine erythroleukemia (MEL) cells, thymus, and stomach the cDNA encoding the Ca 2؉ -gated K ؉ (K Ca ) channel, mIK1, the mouse homolog of hIK1 (Ishii, T. M., Silvia, C., Hirschberg, B., Bond, C. T., Adelman, J. P., and Maylie, J. (1997) Proc. Natl. Acad. Sci.(U. S. A. 94, 11651-11656). mIK1 mRNA was detected at varied levels in many tissue types. mIK1 K Ca channel activity expressed in Xenopus oocytes closely resembled the K ca of red cells (Gardos channel) and MEL cells in its single channel conductance, lack of voltage-sensitivity of activation, inward rectification, and Ca 2؉ concentration dependence. mIK1 also resembled the erythroid channel in its pharmacological properties, mediating whole cell and unitary currents sensitive to low nM concentrations of both clotrimazole (CLT) and its des-imidazolyl metabolite, 2-chlorophenyl-bisphenyl-methanol, and to low nM concentrations of iodocharybdotoxin. Whereas control oocytes subjected to hypotonic swelling remained swollen, mIK1 expression conferred on oocytes a novel, Ca 2؉ -dependent, CLT-sensitive regulatory volume decrease response. Hypotonic swelling of voltage-clamped mIK1-expressing oocytes increased outward currents that were Ca 2؉ -dependent, CLT-sensitive, and reversed near the K ؉ equilibrium potential. mIK1 mRNA levels in ES cells increased steadily during erythroid differentiation in culture, in contrast to other K Ca mRNAs examined. Low nanomolar concentrations of CLT inhibited proliferation and erythroid differentiation of peripheral blood stem cells in liquid culture.Terminal differentiation of erythroid precursor cells is marked by enucleation and reduction in cell volume. A major component of cell volume reduction is achieved by reduction of cell K ϩ content. Mature, circulating erythrocytes retain two major ion transport pathways mediating K ϩ efflux (1). These are: 1) electroneutral K-Cl cotransport and 2) a voltage-insensitive, Ca 2ϩ -activated potassium (K ϩ ) channel of intermediate conductance (2-4), also known as the Gardos channel (5). The Gardos channel is thought to play a major role in volume regulation in normal (6) and sickle (SS) 1 human erythrocytes (7,8).Especially in the chronically hypoxic environment of adherent or trapped sickle cells, the Gardos channel appears to mediate the major component of K ϩ loss from the erythrocyte (9), leading to an increased concentration of intracellular hemoglobin S, and exponentially decreasing the lag time for accelerated hemoglobin S polymerization (10). The Gardos channel's biophysical and pharmacological properties have been characterized in excised inside-out human red cell membrane patches, in which Ca 2ϩ -activated K (K Ca ) currents show inwardly rectifying properties with a unitary slope conductance ranging from 15 to 40 picosiemens, depending on the ionic conditions used (11-13). The channel is sensitive to block by charybdotoxin (14 -16), but insensitive to the SK channel blocker, apamin, and to the K ATP channel blockers, the antihypoglycemic drugs (17). 2Sickle...

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“…In erythrocytes, recruitment of a Ca2 -activated K+ channel balances the internal cation content preventing cell swelling (9), and Ca2-dependent vesiculation contributes to terminate the complement lesion (10).…”

Section: Introductionmentioning

confidence: 99%

Terminal complement complex C5b-9 stimulates mitogenesis in 3T3 cells.

Halperin¹,

Taratuska²,

Nicholson‐Weller³

1993

J. Clin. Invest.

Self Cite

115

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The membrane attack complex of complement (MAC) can induce reversible changes in cell membrane permeability resulting in significant but transient intracellular ionic changes in the absence of cell lysis. Because ion fluxes and cytosolic ionic changes are integral steps in the signaling cascade initiated when growth factors bind to their receptors, we hypothesized that the MAC-induced reversible changes in membrane permeability could stimulate cell proliferation. Using purified terminal complement components we have documented a mitogenic effect of the MAC for quiescent murine 3T3 cells. The MAC enhances the mitogenic effects of serum and PDGF, and also stimulates cell proliferation in the absence of other exogenous growth factors. MAC-induced mitogenesis represents a novel effect of the terminal complement complex that could contribute to focal tissue repair or pathological cell proliferation locally at sites of complement activation. (J. Clin. Invest. 1993.

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Ca2+-activated K+ efflux limits complement-mediated lysis of human erythrocytes.

Cited by 36 publications

References 22 publications

Physiological Roles of the Intermediate Conductance, Ca2+-activated Potassium Channel Kcnn4

Physiological Roles of the Intermediate Conductance, Ca2+-activated Potassium Channel Kcnn4

cDNA Cloning and Functional Characterization of the Mouse Ca2+-gated K+ Channel, mIK1

Terminal complement complex C5b-9 stimulates mitogenesis in 3T3 cells.

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