Calcium-Activated Potassium (KCa) Channels

Calcium-activated potassium channels (KCa channels) selectively allow movement of K+ across biological membranes in response to activation by Ca2+. Two groups have been identified, based on their structural similarities and K+ conductance; BK (KCa1.1; big conductance) channels, and SK and IK channels (KCa2.x; small conductance and KCa3.1; intermediate conductance). They are highly expressed in 'excitable' cells, such as neurons and smooth muscle cells, where they regulate membrane repolarization. KCa channels are involved a wide range of processes including neuronal excitability, synaptic transmission, microvasculature vasodilation, vascular tone and blood pressure modulation, and cell cycle regulation.

Literature (2)
Gene Data


Cat. No. Product Name / Activity
6481 AP 14145 hydrochloride
Negative allosteric modulator of KCa2 (SK) channels
4949 MaxiPost
Potassium channel modulator; exerts subtype-specific effects
3895 NS 309
Positive modulator of KCa2 (SK) and KCa3.1 (IK) channels
4597 NS 8593 hydrochloride
Selective negative modulator of KCa2 (SK) channels; inhibits SK currents
6398 SKA 121
Positive allosteric modulator of KCa3.1 (IK) channels


Cat. No. Product Name / Activity
2665 BMS 191011
Potent KCa1.1 (BK) channel opener
2953 CyPPA
KCa2.2 and KCa2.3 (SK) channel activator
1041 1-EBIO
Epithelial KCa channel activator
5814 GoSlo SR 5-69
KCa1.1 (BK) channel activator
4311 GW 542573X
Selective KCa2.1 (SK) channel activator
4788 NS 11021
KCa1.1 (BK) channel activator
3804 NS 1619
KCa1.1 (BK) channel activator
5276 NS 19504
KCa1.1 (BK) channel activator
3670 SKA 31
KCa3.1 (IK) and KCa2 (SK) channel activator


Cat. No. Product Name / Activity
1652 Apamin
KCa2 (SK) channel blocker
1087 Charybdotoxin
KCa (BK) channel blocker
1086 Iberiotoxin
KCa (BK) channel blocker
5571 Lei-Dab 7
High affinity and selective KCa2.2 (SK) blocker
4864 NS 6180
Potent KCa3.1 (IK) channel blocker
2006 Paxilline
Potent KCa1.1 (BK) channel blocker
4617 Penitrem A
Potent and selective KCa1.1 (BK) channel blocker
2946 TRAM 34
Potent and highly selective KCa3.1 (IK) channel blocker
4952 TRAM 39
Potent KCa3.1 (IK) blocker
1310 UCL 1684
Highly potent KCa2 (SK) channel blocker
2661 UCL 2077
Slow afterhyperpolarization (sAHP) channel blocker; sub-type selective Kv channel effects


Cat. No. Product Name / Activity
Activates Cl- secretion via hKCa3.1 (IK) channel; more potent analog of 1-EBIO (Cat. No. 1041).
5948 DMNPE-4 AM-caged-calcium
Caged calcium; cell permeable

There are 8 members of the KCa channel family, all of which are homo or heterotetramers of α-subunits, with either 6 or 7 transmembrane domains. Some family members also have associated regulatory subunits. KCa1.1 (BK), KCa2.x (SK) and KCa3.1 (IK) ion channels open in response to intracellular Ca2+ levels. Other KCa family members, KCa4.1, KCa4.2 (now known as KNa1.1 and KNa1.2) and KCa5.1 are grouped with KCa1.1 (BK) based on their structural similarities, however relatively little is known about their functional properties. Research suggests that these potassium channels are not Ca2+ sensitive; KNa1.1 and KNa1.2 are thought to be activated by intracellular Na+ and Cl-, while KCa5.1 is activated by internal alkalization (OH-) and so is pH-sensitive.

KCa1.1 BK channels

KCa1.1 (BK) channels (also called Slo1 or Maxi-K channels) are the most extensively studied KCa channels. The hallmark of these channels is sensitivity to charybdotoxin (Cat. No. 1087) and iberiotoxin (Cat. No. 1086), components of scorpion venom. A functional BK channel is composed of four KCa1.1 α-subunits, with up to four regulatory β-subunits and up to four regulatory γ-subunits. The wide range of subunit conformations, combined with alternative splicing of all subunit genes, means there is a high level of functional diversity in endogenous KCa1.1 channels. Subunit arrangement modulates single channel pharmacological properties, channel gating, and channel opening probability upon different stimuli. As well as being sensitive to Ca2+ levels, KCa1.1 channels are also voltage-sensitive.

BK channel structure

Figure 1: Structure of KCa1.1 (BK) channel. Structure taken from PDB. PDBID: 6V35. Tao & MacKinnon (2019) Molecular structures of the human Slo1 K+ channel in complex with beta 4. Elife 8.

The α-subunit of KCa1.1 channels, encoded by the KCNMA1 gene, has 7 transmembrane domains with an extracellular N-terminus, and voltage sensor formed by charged amino acids in the S2, S3 and S4 transmembrane domains. The cytoplasmic C-terminus of each α-subunit has at least three divalent cation binding sites, including two high affinity binding sites for Ca2+ in a negatively charged region of the cytoplasmic tail known as the 'calcium bowl'. KCa1.1 α-subunits additionally have a third, low affinity Ca2+ binding site, which may bind Mg2+ at high concentrations. Binding of Ca2+ induces a conformational change in the channel structure, opening the ion pore and allow K+ to flow out of the cell.

A tetramer of KCa1.1 α-subunits can associate with up to four β-subunits, which can either potentiate (β1 and β4) or inhibit (β2 and β3) K+ conductance. β-subunits have specific tissue distribution patterns and confer signature functional properties on the KCa1.1 channels with which they associate. For example, the β1 subunit is only expressed in smooth muscle, β2 and β3 are expressed in peripheral and central neurons, and β4 is only expressed in the brain. The β4 subunit also modulates channel properties so slow activation occurs at low Ca2+ concentrations. KCa1.1 channels with a β4 subunit display near complete resistance to charybdotoxin (Cat. No. 1087) and iberiotoxin (Cat. No. 1086).

Up to four γ-subunits can also be found in a functional KCa1.1 channel. γ-subunits are proteins of the LRRC superfamily, with a long extracellular domain, a single transmembrane domain and a short cytoplasmic tail. They modulate channel gating and biophysical properties, however relatively little in known about how this occurs.

KCa1.1 channels are ubiquitously expressed in excitable cells, where their function is to repolarize the cell membrane following depolarization. Opening of the ion pore allows K+ to flow out the cell, in response to increased intracellular Ca2+ or depolarization. In neurons, KCa1.1 channels regulate cell excitability, neuronal firing and synaptic transmission. Repolarization following depolarization during an action potential enables rapid, repeated neuronal firing. KCa1.1 channels are also thought to play a role in modulating activity of astrocytes and microglia.

In vascular smooth muscle cells, KCa1.1 channels are involved in myocyte relaxation; mice lacking KCa1.1 channels have increased mean arterial pressure and vascular tone. Protein kinase C (PKC) modulates KCa1.1 channels in smooth muscle cells via phosphorylation, which decreases channel opening probability by shortening channel opening times.

KCa2.x SK Channels

KCa2.x (SK) channels are voltage-insensitive Ca2+ activated K+ channels formed from four subunits, each of which has 6 transmembrane domains and a pore-forming p-loop between S5 and S6. The cytoplasmic C-terminal region of each subunit has a binding site for calmodulin, which is responsible for Ca2+ sensing. Calmodulin is constitutively bound to this region, enabling rapid channel opening in response to changes in intracellular Ca2+ levels. KCa2.x channels can be pharmacologically distinguished from other KCa channels by their sensitivity to apamin (Cat. No. 1652), a toxin from honeybees that acts as a competitive antagonist and physically blocks the ion pore. Phosphorylation of calmodulin by casein kinase 2 (CK2) modulates Ca2+ sensitivity of KCa2.x channels; calmodulin is phosphorylated when the ion pore is closed to reduce Ca2+ sensitivity.

Like KCa1.1 channels, KCa2.x channels are expressed throughout the central nervous system, and are involved in neuronal excitability and synaptic transmission. KCa2.x channels have been shown to control action potential discharge in a wide range of neuronal subtypes including hippocampal, midbrain dopaminergic, cortical and sympathetic neurons. In dendritic spines KCa2.x channels are directly coupled to NMDA receptors and are activated by Ca2+ flowing through these ionotropic glutamate receptors during membrane depolarization.

KCa3.1 IK Channels

KCa3.1 (IK) channels are very similar to KCa2.x channels; they are composed of four, 6-transmembrane domain subunits, are insensitive to voltage and sense Ca2+ via calmodulin bound on the C-terminal regions. However, unlike KCa2.x channels, they are mainly expressed in peripheral tissues, where they are implicated in diverse processes such as vasodilation of microvasculature, phagocytosis by neutrophils, and regulation of cell cycle in cancer cells, B- and T-lymphocytes and stem cells.

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    Ca2+-Activated Potassium Channel Gene Data

    Gene Species Gene Symbol Gene Accession No. Protein Accession No.
    KCa1.1 Human KCNMA1 NM_002247 Q9UBB0
    Mouse Kcnma1 NM_010610 Q08460
    Rat Kcnma1 NM_031828 Q9QWW4
    KCa2.1 Human KCNN1 NM_002248 Q92952
    Mouse Kcnn1 NM_032397 Q9EQR3
    Rat Kcnn1 NM_019313 Q3S915
    KCa2.2 Human KCNN2 NM_021614 Q9H2S1
    Mouse Kcnn2 NM_080465 P58390
    Rat Kcnn2 NM_019314 Q3S914
    KCa2.3 Human KCNN3 NM_002249 Q9UGI6
    Mouse Kcnn3 NM_080466 P58391
    Rat Kcnn3 NM_019315 Q3S913
    KCa3.1 Human KCNN4 NM_002250 O15554
    Mouse Kcnn4 NM_008433 O89109
    Rat Kcnn4 NM_023021 Q3S912
    KCa4.1 Human KCNT1 NM_020822 Q5JUK3
    Mouse Kcnt1 NM_175462 Q6ZPR4
    Rat Kcnt1 NM_021853 Q9Z258
    KCa4.2 Human KCNT2 NM_198503 Q6UVM3
    Mouse Kcnt2 NM_001081027 NP_001074496
    Rat Kcnt2 NM_198762 Q6UVM4
    KCa5.1 Human KCNU1 NM_001031836 A8MYU2
    Mouse Kcnu1 NM_008432 O54982