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Calcium-Activated Potassium Channels
	Introduction
	Contributors
	References
	KCa1.1
	KCa2.1
	KCa2.2
	KCa2.3
	KCa3.1
	KCa4.1
	KCa4.2
	KCa5.1

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K_Ca3.1

Previous and Unofficial Names SK41 Ik1 Gardos channel KCa4 IKCa1 KCa3.1 KCa4 IKCa1 KCa3.1 KCNN4 Structural Information Species TM P Loops AA Chromosomal Location Gene Name Reference Human 6 1 427 19q13.2 KCNN4 8-9,46,121-122 Rat 6 1 424 1q21 Kcnn4 123 Mouse 6 1 425 7 A3 Kcnn4 124

Contents: Previous and Unofficial Names Structural Information Database Links Associated Proteins Ion Selectivity and Conductance Voltage Dependence Activators Gating Inhibitors Pore Blockers Tissue Distribution Functional Assays Physiological Functions Clinically-Relevant Mutations Gene Expression and Pathophysiology

Database Links
ChEMBL Target	10992 (Hs), 100329 (Rn)
Ensembl	ENSG00000104783 (Hs), ENSMUSG00000054342 (Mm), ENSRNOG00000019440 (Rn)
Entrez Gene	3783 (Hs), 16534 (Mm), 65206 (Rn)
GeneCards	KCNN4 (Hs)
HomoloGene	1696 (Hs)
OMIM	602754 (Hs)
PharmGKB Gene	PA222 (Hs)
Protein Ontology (PRO)	PRO:000000700 (Hs)
RefSeq Nucleotide	NM_002250 (Hs), NM_008433 (Mm), NM_023021 (Rn)
RefSeq Protein	NP_002241 (Hs), NP_032459 (Mm), NP_075410 (Rn)
UniGene Hs.	10082 (Hs)
UniProt	O15554 (Hs), O89109 (Mm), Q9QYW1 (Rn)
Wikipedia	KCa3.1

Search for 3D structures on the PDB
Search using keywords: Calcium-Activated Potassium Channels KCa3.1	Search using accession numbers: Q9QYW1 || O15554 || O89109

Associated Proteins
Heteromeric Pore-forming Subunits Name References Not determined	Auxiliary Subunits Name References Not determined	Other Associated Proteins Name References calmodulin 11,125

Ion Selectivity and Conductance
Species:  Human Rank order:  K+ [11.0 - 40.0 pS] > Rb+ > NH4+ > Cs+ References:  8-9,131

Voltage Dependence Comments

KCa3.1 is voltage independent.

Activators
Key to terms and symbols	View all chemical structures	Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference NS309 Hs 8.0 pEC50 - -90.0 40 SKA-31 Hs 6.6 pEC50 - - 152 Ca2+ Hs 6.1 – 7.0 pEC50 - -120.0 – 60.0 8-9,65,122,131 DC-EBIO Hs 6.1 pEC50 - -100.0 149 EBIO Hs 4.1 – 4.5 pEC50 - -100.0 – -50.0 41,65 chlorzoxazone Hs 4.0 pEC50 - -100.0 65 riluzole Hs 5.67 pIC50 - - 152
Activator Comments
No species differences described; NS309, DCEBIO, riluzole and EBIO increase the Ca2+ sensitivity of both KCa3.1 and KCa2 channels; see [42] for recent extensive review of KCa3.1 and KCa2 channel pharmacology

Gating Inhibitor Comments

No gating inhibitors described; the inhibitory gating modulator of KCa2 channels NS8593 does not block KCa3.1 [43]

Pore Blockers
Key to terms and symbols	View all chemical structures	Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference TRAM-34 Hs 7.6 – 8.0 pKd - - 130,134 charybdotoxin-GLU32 analog Hs 7.48 pKd - - 129 clotrimazole Hs 6.41 – 7.62 (median: 7.16) pKd - - 8,121-122,130 nitrendipine Hs 6.05 pKd - - 130 charybdotoxin Hs 8.52 – 8.67 pKi - - 46 maurotoxin Hs 9.0 pIC50 - - 127 charybdotoxin Hs 8.5 pIC50 - - 8-9,122,128,131 ICA-17043 Hs 7.96 pIC50 - - 137 methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-1,4,7-tetrahydroisobenzofuran-5-carboxylate Hs 7.92 – 8.0 pIC50 - - 150-151 nitrendipine Hs 7.57 pIC50 - - 128
Pore Blocker Comments
Many more blockers have been characterised; see [42] for extensive review of pharmacology.

Tissue Distribution
T and B lymphocytes Species:  Human Technique:  Northern Blot, electrophysiology and pharmacology References:  42,46,79,131-133
Proliferating smooth muscle and fibroblasts Species:  Rat Technique:  RT-PCR, Electrophysiology, Immunohistochemistry References:  42,134,140-141,148
Vascular endothelium, lung and colonic endothelium, Paneth cells Species:  Rat Technique:  Electrophysiology, Pharmacology, RT-PCR References:  42,109,142-144
Placenta, lung, pancreas, colon, stomach, prostate, thymus, spleen, lymph node, bone marrow, peripheral blood, but absent from (brain, heart and skeletal muscle) Species:  Human Technique:  Northern Blot References:  8-9,46,122
Erythrocytes Species:  Mouse Technique:  Northern Blot, KCa3.1 knock-out mice References:  124,158
KCa3.1 has been implicated with the proliferation of and found in cancer cell lines: LNCaP and PC-3 prostate cancer cells, leukemic HL-60 cells, glioblastoma GL-15 cells, MCF-7 breast cancer cells, BxPC-3 and MiaPaCa-2 pancreatic cancer cells, HEC-1A and KLE endometrial cancer cells Species:  Human Technique:  Electrophysiology, Pharmacology, RT-PCR References:  159-162

Functional Assays
Two electrode voltage-clamp or whole cell patch-clamp recording of heterologously expressed KCa3.1 (varying concetrations of Ca2+ to activate current in patch-electrode) Species:  Human Tissue:  HEK 293 cells, CHO cells, COS-7 cells, Xenopus oocytes Response measured:  KCa3.1 current References:  8-9,40-41,46,122,127-130
Whole-cell patch-clamp and single channel recordings of KCa3.1 Species:  Human Tissue:  T and B lymphocytes Response measured:  KCa3.1 current References:  46,130-132
Whole-cell patch-clamp and single channel recordings of KCa3.1 Species:  Rat Tissue:  Microglia, proliferating vascular smooth muscle, colonic endothelium Response measured:  KCa3.1 current References:  79,123,133-134
Calcium-dependent K+ or Rb+ flux Species:  Human Tissue:  Erythrocytes Response measured:  K+/Rb+ flux, Gardos "effect" References:  135-137
Endothelium-derived hyperpolarizing factor (EDHF) mediated vasodilation can be measured in various arterial preparations from humans, rats, mice or pigs Species:  Rat Tissue:  Mesenteric, carotid, cerebral, coronary and renal arteries Response measured:  Vasodilation References:  42,109,138

Physiological Functions
Oxidative burst Species:  Rat Tissue:  Microglia References:  79,133
Volume regulation, calcium-dependent dehydration of sickle cell erythrocytes during sickling process, erythrocyte and lymphocyte volume regulation impaired in KCa3.1-/- mouse Species:  Human Tissue:  Erythrocytes (Gardos channel), lymphocytes, osteoblasts References:  125
Hyperpolarization to facilitate calcium influx during cellular proliferation Species:  Human Tissue:  T and B cells, fibroblasts, vascular smooth muscle, vascular endothelial cells (angiogenesis), cancer cell lines References:  46,125,130,132,134,139-141
Involved in fluid and salt transport in secretory epithelia (various species including mouse, rat and rabbit) Species:  Mouse Tissue:  Colonic and lung epithelium, colonic crypts, Panth cells References:  42,123,142-144
Endothelium-derived hyperpolarizing factor (EDHF) mediated vasodilation can be measured in various arterial preparations from humans, rats, mice or pigs, KCa3.1-/- mouse shows reduced EDHF response Species:  Mouse Tissue:  Mesenteric, carotid, cerebral, coronary and renal arteries References:  42,109-110,138,145
Migration Species:  Human Tissue:  Macrophages, microglia (rat), vascular smooth muscle (pig) References:  42,146-148

Clinically-Relevant Mutations
Disease:  Sickle cell anemia Role:  KCa3.1 is involved in erythrocyte dehydration during sickling Drugs:  Clotrimazole, ICA-17043 Side effects:  none reported Theraputic use:  Phase-3 clinical trials for ICA-17043 were stopped in 2007 apparently due to lack of efficacy in reducing the incidence of sickling crisis References:  153-155 Mutations not determined
Disease:  Restenosis and angiogenesis Role:  Involved in T and B cell activation; vascular smooth muscle and endothelial cell proliferation Drugs:  TRAM-34 Side effects:  none reported in mice or rats Theraputic use:  Potential use of KCa3.1 blockers as immunosuppressants and for the prevention of restenosis and angiogenesis References:  42,46,130,134,139,156-157 Mutations not determined
Disease:  Traumatic (and possibly ischemic brain injury) Role:  KCa3.1 is involved in respiratory burst and microglia mediated neuronal killing Drugs:  cyclohexadione 16, TRAM-34 Side effects:  none reported Theraputic use:  KCa3.1 blockers suggested for the treatment of brain injury Comments:  cyclohexadione 16, TRAM-34 efficacy has been demonstrated in rat models of traumatic brain injury or optic nerve transcetion References:  79,133,150 Mutations not determined
Disease:  Not determined References:  Click column headers to sort Type Species Molecular location Reference Deletion Human 19q13.2 121
Clinically-Relevant Mutations Comments
Mutation: Large hemizygous deletion from D19S19 to CYP2B6 on 19q13.2, and Pathophysiology: This deletion was detected in one patient with Diamond-Blackfan anemia DBA

Gene Expression and Pathophysiology
Reduced KCa3.1 expression in carotid artery of uremic rats and regenerated endothelium after ballon catheter injury Tissue or cell type:  Carotid arteries Pathophysiology:  Impaired EDHF response Species:  Rat Technique:  References:  97,126

To cite this receptor data page, please use the following:

George A. Gutman , Richard Aldrich, K. George Chandy, Stephan Grissmer, Aguan D. Wei, Heike Wulff.
Calcium-Activated Potassium Channels: K_Ca3.1. Last modified on 2010-07-01. Accessed on 2010-09-03. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=384.

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