Calcium-activated potassium channel slowpoke-like (K_chnl_Slo-like)
Type: Family

This entry represents a family of calcium-activated potassium channels, known as BK channels (also referred to as high-conductance, maxi-K channels) or Slowpoke homologues (Slo1-3), including calcium-activated potassium channel slowpoke from Drosophila (Slo) and its homologues from vertebrates, namely calcium-activated potassium channel subunit alpha-1 (KCNMA1, also known as BK channel, MaxiK, mSlo1, KCa1.1 or K(VCA)alpha) , KCNT1/2 (Slo2.2/Slo2.1) and KCNU1 (Slo3) from human .

BK channels are widely expressed in the body, being found in glandular tissue, smooth and skeletal muscle, as well as in neural tissues. They have been demonstrated to regulate arteriolar and airway diameter, and also neurotransmitter release. Each channel complex is thought to be composed of 2 types of subunit; the pore-forming (alpha) subunits and smaller accessory (beta) subunits.

The alpha subunit of the BK channel was initially thought to share the characteristic 6TM organisation of the voltage-gated K+ channels. However, the molecule is now thought to possess an additional TM domain, with an extracellular N terminus and intracellular C terminus. This C-terminal region contains 4 predominantly hydrophobic domains, which are also thought to lie intracellularly. The extracellular N terminus and the first TM region are required for modulation by the beta subunit. The precise location of the Ca2+-binding site that modulates channel activation remains unknown, but it is thought to lie within the C-terminal hydrophobic domains.

Mutations in KCNMA1 causing loss of function are associated with multiple malformations and a variety of neurological and developmental phenotypes while gain-of-function mutations are associated with epilepsy and paroxysmal dyskinesia .

Potassium channels are the most diverse group of the ion channel family . They are important in shaping the action potential, and in neuronal excitability and plasticity . The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups : the practically non-inactivating 'delayed' group and the rapidly inactivating 'transient' group.

These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K
+
channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengers . In eukaryotic cells, K
+
channels are involved in neural signalling and generation of the cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs) and may have a role in target cell lysis by cytotoxic T-lymphocytes . In prokaryotic cells, they play a role in the maintenance of ionic homeostasis .

All K
+
channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which has been termed the K
+
selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K
+
across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo-or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K
+
channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K
+
channels; and three types of calcium (Ca)-activated K
+
channels (BK, IK and SK) . The 2TM domain family comprises inward-rectifying K
+
channels. In addition, there are K
+
channel alpha-subunits that possess two P-domains. These are usually highly regulated K
+
selective leak channels.