KCNB1

Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or K_v2.1, is a protein that, in humans, is encoded by the KCNB1 gene.

Potassium voltage-gated channel subfamily B member one, or simply known as KCNB1, is a delayed rectifier and voltage-gated potassium channel found throughout the body. The channel has a diverse number of functions. However, its main function, as a delayed rectifier, is to propagate current in its respective location. It is commonly expressed in the central nervous system, but may also be found in pulmonary arteries, auditory outer hair cells, stem cells, the retina, and organs such as the heart and pancreas. Modulation of K+ channel activity and expression has been found to be at the crux of many profound pathophysiological disorders in several cell types.

Potassium channels are among the most diverse of all ion channels in eukaryotes. With over 100 genes coding numerous functions, many isoforms of potassium channels are present in the body, but most are divided up into two main groups: inactivating transient channels and non-inactivating delayed rectifiers. Due to the multiple varied forms, potassium delayed rectifier channels open or close in response to a myriad of signals. These include: cell depolarization or hyperpolarization, increases in intracellular calcium concentrations, neurotransmitter binding, or second messenger activity such as G-proteins or kinases.

The general structure of all potassium channels contain a centered pore composed of alpha subunits with a pore loop expressed by a segment of conserved DNA, T/SxxTxGxG. This general sequence comprises the selectivity of the potassium channel. Depending on the channel, the alpha subunits are constructed in either a homo- or hetero-association, creating a 4-subunit selectivity pore or a 2-subunit pore, each with accessory beta subunits attached intracellularly. Also on the cytoplasmic side are the N- and C- termini, which play a crucial role in activating and deactivating KCNB1 channels. This pore creates the main opening of the channel where potassium ions flow through.

The type of pore domain (number of subunits) determines if the channel has the typical 6 transmembrane (protein) spanning regions, or the less dominant inward rectifier type of only 2 regions. KCNB1 has 6TM labeled S1-S6, each with a tetrameric structure. S5 and S6 create the p-loop, while S4 is the location of the voltage sensor. S4, along with S2 and S3 create the ‘activating’ portions of the delayed rectifier channel. The heteromeric complexes that contain the distinct pore are electrically inactive or non-conducting, but unlike other potassium families, the pore of the KCNB1 group has numerous phosphorylation sites allowing kinase activity. Maturing KCNB1 channels develop these phosphorylation sites within the channel pore, but lack a glycosylation stage in the N-terminus.

Specifically, the KCNB1 delayed rectifier channel conducts a potassium current (K+). This mediates high frequency firing due to the phosphorylation sites located within the channel via kinases and a major calcium influx typical of all neurons.

The kinetics surrounding the activation and deactivation of the KCNB1 channel is relatively unknown, and has been under considerable study. Three of the six transmembrane regions, S2, S3 and S4, contribute to the activation phase of the channel. Upon depolarization, the S4 region, which is positively charged, is moved in response to the subsequent positive charge of the depolarization. As a result of S4 movement, the negatively charged regions of S2 and S3 appear to move as well. The movement of these regions causes an opening of the channel gate within regions of S5 and S6. The intracellular regions of the C and N-terminus also play a crucial role in the activation kinetics of the channel. The two termini interact with one other, as the C-terminus folds around the N-terminus during channel activation. The relative movement between the N- and C- termini greatly aids in producing a conformational change of the channel necessary for channel opening. This interaction between these intracellular regions is believed to be linked with membrane-spanning regions of S1 and S6, and thus aid in the movement of S2, S3, and S4 in opening the channel. Studies on selective mutations knocking out these intracellular termini have been shown to produce larger reductions in speed and probability of channel opening, which indicates their importance in channel activation.

Voltage-gated potassium (K_v) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Delayed rectifier potassium channels’ most prevalent role is in the falling phase of physiological action potentials. KCNB1 rectifiers are also important in forming the cardiac beat and rate synchronicity that exists within the heart, and the lysis of target molecules in the immune response. These channels can also act as effectors in downstream signaling in G-protein coupled receptor transduction. KCNB1's regulation and propagation of current provides a means for regulatory control over several physiological functions. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and apoptosis.