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• W4307137401 abstract "The intermediate‐conductance, calcium‐activated potassium channel KCa3.1, first cloned in 1997,1.Ishii T.M. Silvia C. Hirschberg B. Bond C.T. Adelman J.P. Maylie J. A human intermediate conductance calcium‐activated potassium channel.Proc Natl Acad Sci U S A. 1997; 94: 11651-11656Crossref PubMed Scopus (512) Google Scholar is also known as IK, IKCa, SK4, KCNN4 or due to its role in erythrocyte volume regulation as the Gárdos channel.2.Gardos G. The function of calcium in the potassium permeability of human erythrocytes.Biochem Biophys Acta. 1958; 30: 653-654Crossref PubMed Scopus (468) Google Scholar, 3.Vandorpe D.H. Shmukler B.E. Jiang L. et al.cDNA cloning and functional characterization of the mouse Ca2+‐gated K+ channel, mIK1. Roles in regulatory volume decrease and erythroid differentiation.J Biol Chem. 1998; 273: 21542-21553Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar KCa3.1 channels are widely expressed in non‐excitable tissues such as red and white blood cells, proliferating smooth muscle and fibroblasts, vascular endothelium, and secretory epithelia.4.Brown B.M. Shim H. Christophersen P. Wulff H. Pharmacology of small‐ and intermediate‐conductance calcium‐activated potassium channels.Annu Rev Pharmacol Toxicol. 2020; 60: 219-240Crossref PubMed Scopus (45) Google Scholar Based on their ability to hyperpolarize the cell membrane upon elevation of intracellular calcium concentration ([Ca2+]i), KCa3.1 channels regulate calcium signaling and downstream processes such as activation, proliferation, and secretion.4.Brown B.M. Shim H. Christophersen P. Wulff H. Pharmacology of small‐ and intermediate‐conductance calcium‐activated potassium channels.Annu Rev Pharmacol Toxicol. 2020; 60: 219-240Crossref PubMed Scopus (45) Google Scholar Whereas KCa3.1 inhibitors have been widely studied as immunosuppressants or anti‐fibrotic agents and even advanced into clinical trials for asthma and sickle cell anemia,5.Ataga K.I. Smith W.R. De Castro L.M. et al.Efficacy and safety of the Gardos channel blocker, senicapoc (ICA‐17043), in patients with sickle cell anemia.Blood. 2008; 111: 3991-3997Crossref PubMed Scopus (172) Google Scholar, 6.Ataga K.I. Staffa S.J. Brugnara C. Stocker J.W. Haemoglobin response to senicapoc in patients with sickle cell disease: a re‐analysis of the Phase III trial.Br J Haematol. 2021; 19: e129-e132Google Scholar KCa3.1 activators have been proposed as endothelial‐targeted antihypertensives and as enhancers of fluid secretion in cystic fibrosis.4.Brown B.M. Shim H. Christophersen P. Wulff H. Pharmacology of small‐ and intermediate‐conductance calcium‐activated potassium channels.Annu Rev Pharmacol Toxicol. 2020; 60: 219-240Crossref PubMed Scopus (45) Google Scholar Working with human platelets, Back and colleagues are proposing inhibition of platelet aggregation as a novel possible therapeutic indication for KCa3.1 activators in this issue of the Journal of Thrombosis and Hemostasis. Platelets have been known to express KCa channels with biophysical properties resembling KCa3.1 since 1995, when Mahaut‐Smith et al. reported KCa currents in human platelets subjected to perforated whole‐cell patch‐clamp recordings.7.Mahaut‐Smith M.P. Calcium‐activated potassium channels in human platelets.J Physiol (Lond). 1995; 484: 15-24Crossref Scopus (40) Google Scholar However, possible roles of these channels in platelet adhesion and aggregation remained uninvestigated. Using a combination of aggregometry, confocal microscopy, flow cytometry and an innovative application of a flow chamber model, the Quartz Crystal Microbalance (QCM), Back et al. are now confirming that human platelets express KCa3.1 channels. They further demonstrate that the KCa3.1 positive gating modulator SKA‐318.Sankaranarayanan A. Raman G. Busch C. et al.Naphtho[1,2‐d]thiazol‐2‐ylamine (SKA‐31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium‐derived hyperpolarizing factor response and lowers blood pressure.Mol Pharmacol. 2009; 75: 281-295Crossref PubMed Scopus (164) Google Scholar inhibits collagen‐induced or ADP‐induced platelet aggregation. This SKA‐31 effect on platelet aggregation is concentration dependent, mediated by membrane hyperpolarization, and blocked by the KCa3.1 inhibitor TRAM‐34,9.Wulff H. Miller M.J. Haensel W. Grissmer S. Cahalan M.D. Chandy K.G. Design of a potent and selective inhibitor of the intermediate‐conductance Ca2+‐activated K+ channel, IKCa1: a potential immunosuppressant.Proc Natl Acad Sci U S A. 2000; 97: 8151-8156Crossref PubMed Scopus (532) Google Scholar but not by the KCa2 channel inhibitor apamin. Experiments employing the QCM flow chamber revealed that SKA‐31 prevented platelet aggregation on collagen‐coated quartz crystals under both high and low flow conditions as effectively as the P2Y12 receptor antagonist ticagrelor. However, SKA‐31 was without effect on platelet adhesion to fibrinogen, consistent with greater inhibition of aggregation than of adhesion. Further investigation into the mechanism of action of SKA‐31 showed that KCa3.1 activation reduced the rise in intracellular calcium that accompanies collagen‐induced platelet aggregation, suggesting that KCa3.1 activation limits calcium entry through voltage‐gated calcium channels by inducing membrane hyperpolarization (Figure 1). In addition, SKA‐31‐mediated activation of platelet KCa3.1 reduced surface exposure of P‐selectin, activation of αIIb/β3 integrin, and secretion of PDGF‐containing α granules and of ATP‐containing dense granules, without altering release of nitric oxide. However, in the hands of the authors, SKA‐31 enhanced rather than reduced both surface exposure of phosphatidylserine (PS) and platelet binding of coagulation factor V, suggesting that KCa3.1 activators should suppress platelet aggregation without inhibiting coagulation. SKA‐31, like its derivative SKA‐111,10.Shim H. Brown B.M. Singh L. et al.The trials and tribulations of structure assisted design of KCa channel activators.Front Pharmacol. 2019; 10: 972Crossref PubMed Scopus (13) Google Scholar probably binds to KCa3.1 at the interface between the S4‐S5 linker and the N‐lobe of the channel‐associated calmodulin. As calmodulin is a constitutively associated β‐subunit of KCa3.1,4.Brown B.M. Shim H. Christophersen P. Wulff H. Pharmacology of small‐ and intermediate‐conductance calcium‐activated potassium channels.Annu Rev Pharmacol Toxicol. 2020; 60: 219-240Crossref PubMed Scopus (45) Google Scholar the authors' proposal that SKA‐31 induces calmodulin “steal” from other proteins such as eNOS seems somewhat unlikely, and will require further experimental verification. However, the inhibitory effects of pharmacological KCa3.1 activation on platelet calcium signaling and aggregation are convincingly demonstrated by Back et al. in this important “pioneering” study and should inspire both translational animal studies and more detailed mechanistic experiments, including elucidation of the Ca2+ entry pathways regulated by KCa3.1. As the authors point out in their discussion, the recent discoveries of T‐type calcium channels in platelets and of delayed thrombus formation in CaV3.2−/− mice11.Tamang H.K. Yang R.B. Song Z.H. et al.Cav 3.2 T‐type calcium channel regulates mouse platelet activation and arterial thrombosis.J Thromb Haemost. 2022; 20: 1887-1899Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar clearly warrant reexamination of the spectrum of voltage‐gated calcium channel (CaV) expression in platelets. Given that KCa3.1 channels regulate T cell calcium influx through the inward‐rectifier calcium channel Orai1 (CRACM1),12.Feske S. Wulff H. Skolnik E.Y. Ion channels in innate and adaptive immunity.Annu Rev Immunol. 2015; 33: 291-353Crossref PubMed Scopus (393) Google Scholar the importance of the various calcium sources in regulation of platelet aggregation should be examined. For example, Orai1 is known to mediate store‐operated calcium entry in human and mouse platelets, and Orai1 deficiency in mice results in resistance to pulmonary thromboembolism and arterial thrombosis, accompanied by minimal prolongation of bleeding time.13.Braun A. Varga‐Szabo D. Kleinschnitz C. et al.Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation.Blood. 2009; 113: 2056-2063Crossref PubMed Scopus (209) Google Scholar If Orai1 serves as the dominant Ca2+ entry pathway in platelets, membrane hyperpolarization should enhance calcium influx. However, Back et al. observed reduced rather than enhanced collagen‐induced Ca2+ signaling in platelets treated with the KCa3.1 activator SKA‐31, presumably reflecting hyperpolarization‐induced closure of CaV channels with resultant decreased Ca2+ influx. From a therapeutic perspective, it would be important to take a closer look at the effects of KCa3.1 modulators on platelet function and coagulation. The current study and a previous report14.Wolfs J.L. Wielders S.J. Comfurius P. et al.Reversible inhibition of the platelet procoagulant response through manipulation of the Gardos channel.Blood. 2006; 108: 2223-2228Crossref PubMed Scopus (43) Google Scholar agree that KCa3.1 inhibitors neither potentiate nor inhibit platelet aggregation, which is “good news” for ongoing attempts to repurpose the KCa3.1 blocker senicapoc for treatment of Alzheimer’s disease15.Jin L.W. Di Lucente J. Nguyen H.M. et al.Repurposing the KCa3.1 inhibitor senicapoc for Alzheimer's disease.Ann Clin Transl Neurol. 2019; 18: 723-738Crossref Scopus (27) Google Scholar and of hereditary xerocytosis, a hemolytic anemia caused by gain of function mutations in KCa3.1.16.Glogowska E. Lezon‐Geyda K. Maksimova Y. Schulz V.P. Gallagher P.G. Mutations in the Gardos channel (KCNN4) are associated with hereditary xerocytosis.Blood. 2015; 126: 1281-1284Crossref PubMed Scopus (77) Google Scholar, 17.Andolfo I. Russo R. Manna F. et al.Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis).Am J Hematol. 2015; 90: 921-926Crossref PubMed Scopus (63) Google Scholar However, the most exciting therapeutic implication of the study by Back et al. is that selective and potent KCa3.1 activators may have a better efficacy and safety profile than current anti‐platelet agents by inhibiting platelet aggregation while maintaining procoagulant responses and thus may not increase the risk of bleeding. KCa3.1 activators would further be expected to exert beneficial effects on the vascular endothelium where KCa3.1 channels mediate the endothelium‐derived hyperpolarization response and have been shown to lower blood pressure,18.Brahler S. Kaistha A. Schmidt V.J. et al.Genetic deficit of SK3 and IK1 channels disrupts the endothelium‐derived hyperpolarizing factor vasodilator pathway and causes hypertension.Circulation. 2009; 119: 2323-2332Crossref PubMed Scopus (200) Google Scholar, 19.Damkjaer M. Nielsen G. Bodendiek S. et al.Pharmacological activation of KCa3.1/KCa2.3 channels produces endothelial hyperpolarization and lowers blood pressure in conscious dogs.Br J Pharmacol. 2012; 165: 223-234Crossref PubMed Scopus (58) Google Scholar and normalize endothelial dysfunction in type 2 diabetes and aging.20.John C.M. Khaddaj Mallat R. Mishra R.C. et al.SKA‐31, an activator of Ca2+‐activated K+ channels, improves cardiovascular function in aging.Pharmacol Res. 2020; 151Crossref PubMed Scopus (8) Google Scholar, 21.Mishra R.C. Kyle B.D. Kendrick D.J. et al.KCa channel activation normalizes endothelial function in Type 2 Diabetic resistance arteries by improving intracellular Ca2+ mobilization.Metabolism. 2021; 114Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Risk of arterial thrombosis is elevated by factors such as hypercholesterolemia, diabetes, sedentary lifestyle, obesity, poor diet, and high blood pressure, suggesting that relevant animal models of such conditions may provide novel opportunities to investigate the effects of KCa3.1 channel activators on platelet aggregation and coagulation in pre‐clinical settings. Indeed, prolonged daily administration of SKA‐31 (10 mg/kg) to aged rats (18–20 months) was not associated with deleterious effects,20.John C.M. Khaddaj Mallat R. Mishra R.C. et al.SKA‐31, an activator of Ca2+‐activated K+ channels, improves cardiovascular function in aging.Pharmacol Res. 2020; 151Crossref PubMed Scopus (8) Google Scholar suggesting that this class of drug may be well tolerated. Whether KCa3.1 activators will have similar effects on the behavior of platelets derived from pathophysiological models of cardiovascular disease is an important consideration for future investigation. On a cautionary note, on‐target activity of SKA‐31 may produce unwanted side effects, making KCa3.1 activators inappropriate or contraindicated in some clinical settings. Potential hyperkalemia caused by release of intracellular K+ should not be problematic when renal function and tissue K+ buffering are normal. However, caution should be exercised when considering use of KCa3.1 activators in the settings of renal insufficiency or of known cardiac arrhythmias. Although potentially useful as anti‐hypertensives, KCa3.1 activators should be examined for their effects on vascular autoregulation, inhibition of which in the elderly may predispose them to postural hypotension, gait imbalance, and falls. As Back et al. show that nifedipine potentiates the inhibitory effect of SKA‐31 on platelet aggregation, such postural hypotension might be aggravated in coronary insufficiency patients treated with calcium channel antagonists. Hyperactivity of erythrocyte KCa3.1 in sickle cell disease leads to red cell dehydration and acceleration of hypoxia‐induced red cell sickling.22.Brugnara C. Sickle cell dehydration: pathophysiology and therapeutic applications.Clin Hemorheol Microcirc. 2018; 68: 187-204Crossref PubMed Scopus (21) Google Scholar And as mentioned above, the KCa3.1 inhibitor senicapoc was investigated as a treatment for sickle cell anemia and may serve as a useful adjunct therapy in sickle cell disease by preventing red cell dehydration.5.Ataga K.I. Smith W.R. De Castro L.M. et al.Efficacy and safety of the Gardos channel blocker, senicapoc (ICA‐17043), in patients with sickle cell anemia.Blood. 2008; 111: 3991-3997Crossref PubMed Scopus (172) Google Scholar, 6.Ataga K.I. Staffa S.J. Brugnara C. Stocker J.W. Haemoglobin response to senicapoc in patients with sickle cell disease: a re‐analysis of the Phase III trial.Br J Haematol. 2021; 19: e129-e132Google Scholar Thus, use of KCa3.1 activators may be inadvisable in this condition, as well as in other hereditary hemolytic anemias associated with increased membrane cation permeability.23.Vandorpe D.H. Shmukler B.E. Ilboudo Y. et al.A Grammastola spatulata mechanotoxin‐4 (GsMTx4)‐sensitive cation channel mediates increased cation permeability in human hereditary spherocytosis of multiple genetic etiologies.Haematologica. 2021; 106: 2759-2762Crossref PubMed Scopus (3) Google Scholar In conclusion, Beck et al. generated an exciting, new therapeutic hypothesis with their study describing that KCa3.1 activators can reduce platelet aggregation without inhibiting coagulation. As with every new target, it will now take years of mechanistic and translational studies to determine the risk profile of KCa3.1 activation and carefully weigh additional positive effects on the vascular endothelium versus potential negative effects on erythrocyte volume against each other. However, selective KCa3.1 activators, that show no cross‐reactivity to neuronal KCa2 channels, certainly have the potential to be developed into platelet aggregation inhibitors with a low risk of associated bleeding. HW provided the first draft and then all three authors commented and added text and points for consideration. The authors declare no competing conflicts of interest." @default.
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• W4307137401 title "Can KCa3.1 channel activators serve as novel inhibitors of platelet aggregation?" @default.
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