Calcium-Activated Potassium (K_Ca) Channels

There are 8 members of the K_Ca 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. K_Ca1.1 (BK), K_Ca2.x (SK) and K_Ca3.1 (IK) ion channels open in response to intracellular Ca²⁺ levels. Other K_Ca family members, K_Ca4.1, K_Ca4.2 (now known as K_Na1.1 and K_Na1.2) and K_Ca5.1 are grouped with K_Ca1.1 (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; K_Na1.1 and K_Na1.2 are thought to be activated by intracellular Na⁺ and Cl^-, while K_Ca5.1 is activated by internal alkalization (OH^-) and so is pH-sensitive.

K_Ca1.1 BK channels

K_Ca1.1 (BK) channels (also called Slo1 or Maxi-K channels) are the most extensively studied K_Ca 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 K_Ca1.1 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 K_Ca1.1 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, K_Ca1.1 channels are also voltage-sensitive.

Figure 1: Structure of K_Ca1.1 (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 K_Ca1.1 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'. K_Ca1.1 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 K_Ca1.1 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 K_Ca1.1 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. K_Ca1.1 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 K_Ca1.1 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.

K_Ca1.1 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, K_Ca1.1 channels regulate cell excitability, neuronal firing and synaptic transmission. Repolarization following depolarization during an action potential enables rapid, repeated neuronal firing. K_Ca1.1 channels are also thought to play a role in modulating activity of astrocytes and microglia.

In vascular smooth muscle cells, K_Ca1.1 channels are involved in myocyte relaxation; mice lacking K_Ca1.1 channels have increased mean arterial pressure and vascular tone. Protein kinase C (PKC) modulates K_Ca1.1 channels in smooth muscle cells via phosphorylation, which decreases channel opening probability by shortening channel opening times.

K_Ca2.x SK Channels

K_Ca2.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. K_Ca2.x channels can be pharmacologically distinguished from other K_Ca 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 K_Ca2.x channels; calmodulin is phosphorylated when the ion pore is closed to reduce Ca²⁺ sensitivity.

Like K_Ca1.1 channels, K_Ca2.x channels are expressed throughout the central nervous system, and are involved in neuronal excitability and synaptic transmission. K_Ca2.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 K_Ca2.x channels are directly coupled to NMDA receptors and are activated by Ca²⁺ flowing through these ionotropic glutamate receptors during membrane depolarization.

K_Ca3.1 IK Channels

K_Ca3.1 (IK) channels are very similar to K_Ca2.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 K_Ca2.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.

External sources of pharmacological information for Calcium-Activated Potassium (K_Ca) Channels :

• IUPHAR Receptor Code

Ca²⁺-Activated Potassium Channel Gene Data