SK channels are a subfamily of Ca²⁺-activated K⁺ channels. They are so called because of their small single channel conductance, ~10 pS. SK channels are a type of ion channel

Ion channel

Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...

 allowing potassium

Potassium

Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...

 cations to cross the cell membrane and are activated (opened) by an increase in the concentration of intracellular calcium. Their activation limits the firing frequency of action potential

Action potential

In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

s and are important for regulating afterhyperpolarization

Afterhyperpolarization

Afterhyperpolarization or AHP describes the hyperpolarization phase of a neuron's action potential where the cell's membrane potential falls below the normal resting potential. This is also commonly referred to as an action potential's undershoot phase...

 in central neurons and other types of electrically excitable cells. SK channels are thought to be involved in synaptic plasticity

Synaptic plasticity

In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...

 and therefore play important roles in memory and learning.

Structure

SK potassium channels share the same basic architecture with shaker-like voltage-gated potassium channel

Voltage-gated potassium channel

Voltage-gated potassium channels are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state....

s. Four subunits associate to form a tetramer. Each of the subunits has six hydrophobic alpha helical

Alpha helix

A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...

 domains which insert into the cell membrane. A loop between the fifth and sixth transmembrane domain forms the potassium ion selectivity filter. SK channels may assemble as homoterameric channels or as heterotetrameric channels, consisting of more than one SK channel subtype. In addition, SK potassium channels are tightly associated with the protein calmodulin

Calmodulin

Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...

 which accounts for the calcium sensitivity of these channels.

Classification

The SK channel family contains 4 members - SK1

KCNN1

Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 1 , also known as KCNN1 is a human gene encoding the KCa2.1 protein.-Further reading:...

, SK2

KCNN2

Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2, also known as KCNN2, is a protein which in humans is encoded by the KCNN2 gene...

, SK3

SK3

SK3 is a small-conductance calcium-activated potassium channel partly responsible for the calcium-dependent after hyperpolarisation current . It belongs to a family of channels known as small-conductance potassium channels, which consists of three members – SK1, SK2 and SK3 , which share a 60-70%...

, and SK4

KCNN4

Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4, also known as KCNN4, is a human gene encoding the KCa3.1 protein.- Function :...

. SK4 is often referred to as IK (Intermediate conductance) due to its higher conductance 20 - 80 pS.

Channel

Gene

Aliases

Associated subunits >- | SK1 KCNN1 Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 1 , also known as KCNN1 is a human gene encoding the KCa2.1 protein.-Further reading:...

Kca2.1

calmodulin Calmodulin Calmodulin is a calcium-binding protein expressed in all eukaryotic cells... >- | SK2 KCNN2 Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2, also known as KCNN2, is a protein which in humans is encoded by the KCNN2 gene...

Kca2.2

>- | SK3 SK3 SK3 is a small-conductance calcium-activated potassium channel partly responsible for the calcium-dependent after hyperpolarisation current . It belongs to a family of channels known as small-conductance potassium channels, which consists of three members – SK1, SK2 and SK3 , which share a 60-70%...

Kca2.3

>- | SK4 KCNN4 Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4, also known as KCNN4, is a human gene encoding the KCa3.1 protein.- Function :...

Kca3.1

Blockers

All SK channels can be pharmacologically blocked by quaternary ammonium salts of a plant-derived neurotoxin bicuculline

Bicuculline

Bicuculline is a light-sensitive competitive antagonist of GABAA receptors. It was originally identified in 1932 in plant alkaloid extracts and has been isolated from Dicentra cucullaria, Adlumia fungosa, Fumariaceae, and several Corydalis species. Since it blocks the inhibitory action of GABA...

. In addition, SK channels(SK1-SK3) are sensitive to blockade by the bee

Bee

Bees are flying insects closely related to wasps and ants, and are known for their role in pollination and for producing honey and beeswax. Bees are a monophyletic lineage within the superfamily Apoidea, presently classified by the unranked taxon name Anthophila...

 venom

Venom

Venom is the general term referring to any variety of toxins used by certain types of animals that inject it into their victims by the means of a bite or a sting...

 apamin

Apamin

Apamin is an 18 amino acid peptide neurotoxin found in apitoxin . It selectively blocks SK channels, a type of Ca2+-activated K+ channel expressed in the central nervous system and smooth muscle...

, but SK4 (IK) is not. and the scorpion

Scorpion

Scorpions are predatory arthropod animals of the order Scorpiones within the class Arachnida. They have eight legs and are easily recognized by the pair of grasping claws and the narrow, segmented tail, often carried in a characteristic forward curve over the back, ending with a venomous stinger...

 venom tamapin

Tamapin

Tamapin is a toxin from the Indian Red Scorpion , which is a selective and potent blocker of SK2 channels.- Chemical structure & methods of isolation :...

.

Modulators

Allosteric modulators of SK channels work by changing the apparent calcium sensitivity of the channels. Examples include:

• Non selective positive modulators of SK channels: EBIO (1-Ethyl-2-BenzimIdazolinOne), NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime)
• SK-3 selective positive modulators : CyPPA (NS6277; Cyclohexyl-(2-(3,5-dimethyl-Pyrazol-1-yl)-6-methyl-Pyrimidin-4-yl)-Amine)