SK channel

SK channels (small conductance calcium-activated potassium channels) are a subfamily of Ca2+-activated K+ channels. They are so called because of their small single channel conductance in the order of 10 pS. SK channels are a type of ion channel allowing potassium cations to cross the cell membrane and are activated (opened) by an increase in the concentration of intracellular calcium through N-type calcium channels. Their activation limits the firing frequency of action potentials and is important for regulating afterhyperpolarization in the neurons of the central nervous system as well as many other types of electrically excitable cells. This is accomplished through the hyperpolarizing leak of positively charged potassium ions along their concentration gradient into the extracellular space. This hyperpolarization causes the membrane potential to become more negative. SK channels are thought to be involved in synaptic plasticity and therefore play important roles in learning and memory. SK channels (small conductance calcium-activated potassium channels) are a subfamily of Ca2+-activated K+ channels. They are so called because of their small single channel conductance in the order of 10 pS. SK channels are a type of ion channel allowing potassium cations to cross the cell membrane and are activated (opened) by an increase in the concentration of intracellular calcium through N-type calcium channels. Their activation limits the firing frequency of action potentials and is important for regulating afterhyperpolarization in the neurons of the central nervous system as well as many other types of electrically excitable cells. This is accomplished through the hyperpolarizing leak of positively charged potassium ions along their concentration gradient into the extracellular space. This hyperpolarization causes the membrane potential to become more negative. SK channels are thought to be involved in synaptic plasticity and therefore play important roles in learning and memory. SK channels are expressed throughout the central nervous system. They are highly conserved in mammals as well as in other organisms such as Drosophila melanogaster and Caenorhabditis elegans. SK channels are specifically involved in the medium afterhyperpolarizing potential (mAHP). They affect both the intrinsic excitability of neurons and synaptic transmission. They are also involved in calcium signaling. SK channels control action potential discharge frequency in hippocampal neurons, midbrain dopaminergic neurons, dorsal vagal neurons, sympathetic neurons, nucleus reticularis thalmic neurons, inferior olive neurons, spinal and hypoglossal motoneurons, mitral cells in the olfactory bulb, and cortical neurons. SK potassium channels share the same basic architecture with Shaker-like voltage-gated potassium channels. Four subunits associate to form a tetramer. Each of the subunits has six transmembrane hydrophobic alpha helical domains (S1-S6). A loop between S5 and S6—called the P-loop—provides the pore-forming region that always faces the center of the channel. Each of the subunits has six hydrophobic alpha helical domains that insert into the cell membrane. A loop between the fifth and sixth transmembrane domains forms the potassium ion selectivity filter. SK channels may assemble as homotetrameric 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, which accounts for the calcium sensitivity of these channels. Calmodulin participates as a subunit of the channel itself, bound to the cytoplasmic C-terminus region of the peptide called the calmodulin binding domain (CaMBD). Additional association of the phosphorylating kinase CK2 and dephosphorylating phosphatase PP2A on the cytoplasmic face of the protein allow for enriched Ca2+-sensitivity—and thus—kinetics modulation. CK2 serves to phosphorylate the SKCa-bound CaM at the T80 residue, rather than the channel helices themselves, to reduce calcium sensitivity. This may only be accomplished when the channel pore is closed. PP2A dephosphorylates this residue upon CK2 inhibition. The selectivity filter of all SK channel subtypes—whether SK1, SK2, SK3, or SK4—is highly conserved and reflects the selectivity seen in any potassium channel, a GYGD amino acid residue sequence on the pore-forming loop. These channels are considered to be voltage-independent, as they possess only two of seven positively charged amino acid residues that are typically seen in a prototypical voltage-gated potassium channel. The SK channel family contains 4 members – SK1, SK2, SK3, and SK4. SK4 is often referred to as IK (Intermediate conductance) due to its higher conductance 20 – 80 pS. The SK channel gating mechanism is controlled by intracellular calcium levels. Calcium enters the cell via voltage activated calcium channels as well as through NMDA receptors. Calcium does not directly bind to the SK channel. Calcium binds to the protein calmodulin (CaM). When bound to calcium, CaM binds to the CaM-binding domain on the intracellular subunit of the SK channel. When each of the four CaM-binding domain subunits is bound to calmodulin, the SK channel changes conformation. This transitions the channel from a tetramer of monomers to a folded dimer of dimers, which results in rotation of the CaM-binding domains. This rotation causes the mechanical opening of the channel gate. The time constant of SK channel activation is approximately 5 ms. When calcium levels are depleted, the time constant for channel deactivation ranges from 15–60 ms. All SK channels can be pharmacologically blocked by quaternary ammonium salts of a plant-derived neurotoxin bicuculline. In addition, SK channels (SK1-SK3) but not SK4 (IK) are sensitive to blockade by the bee toxin apamin, and the scorpion venoms tamapin and charybdotoxin (ChTx), all via competitive antagonism for access to the mouth of the pore formation. All known blockers compete for roughly the same binding site, the pore, in all subtypes. This provides a physical blockage to the channel pore. Since all blockers are universal to all three types of SK channels, there is an incredibly narrow therapeutic window that does not allow for blocking of a specific SK channel subtype. Quaternary ammonium salts like bicuculline and tetraethylammonium (TEA) enter the pore via the selectivity filter by acting as a potassium mimic in the dehydration step of pore permeation. The following molecules are other toxins and organic compounds that also inhibit all three small SK channel subtypes to any (even minimal) degree: