Research Area

Potassium Channel


Introduction of potassium channel

The ion channel is a cell-specific amphiphilic membrane integrin that selectively interacts with ions through the side chain of the residue to exert a specific permeability barrier function. Ion channels are closely related to a variety of life activities and are also important targets for drug design. Since the use of cell patch clamp and single-channel recording technology, artificial membrane ion channel reconstruction technology, gene recombination technology, channel protein separation, purification and other biochemical techniques have made the molecular structure of many channel proteins gradually clear, and its cDNA has been cloned. It is currently believed that the K+ channel is the most diverse ion channel in the ion channel. The research results show that there are two families of K + channels, and their structure and function are different. Molecular biology and gene recombination techniques also provide an effective way for the study of ion channels. X-ray crystallography provides a visual image for the structural study of K+ channels. With the study of K+ channels, there are still some issues to be further explored, such as subunit function, gene mutation and disease inconsistency. Due to the complexity and diversity of the K+ channel itself, there are certain limitations in the understanding of some K+ structures and functions. Multidisciplinary cross-disciplinary research and advanced technical methods explore the mechanisms of certain diseases or conditions. It is of great theoretical and practical significance to explore the mechanisms of potassium channel in certain diseases and research on K+ channels has received increasing attention in the life sciences.

The classification of potassium channel and their molecule structure

The research results show that the K+ channel has two families, and its structure and function are different. Throughout the history of K+ channel research, there are different classification methods, and the classification bases are conductivity, voltage and current characteristics, biological germline, channel molecular structure, amino acid sequence, and channel protein homology. In mammals, K+ channels are divided into two major families, the family of voltage-gated channels and the family of inward rectifier channels, which have significant differences in their structural features and functions. Voltage-gated K+ channel is a six-transmembrane structure. After 6 passes (S1-S2), a layer of H5 corresponding to the P segment of the sodium channel is sandwiched between S5 and S6. Each channel has 4 such repeated components. This basic structure is the same as the Na+ and Ca2+ channels. The activation gate of the channel is also composed of four S4s. The difference is that the potassium channel contains 1 or 2 functional regions per subunit. Voltage Gated K+ channels, also known as voltage-dependent K+ channels (Kv), are the most known family of ion channels. It can be divided into three categories: 1. delayed rectifier. Hodgkin and other found the K + channels found in the giant axon of the squid belong to this category. When the membrane is depolarized, it is activated by a delay and the deactivation is slow. Time ranges from hundreds of milliseconds to tens of seconds. 2. Type A transient K+ channel (KA) and drug-sensitive M channel. Type A transient K+ channel (KA) was originally named by Conner and Stevens in the rabbit neurons. Its activation and inactivation are rapid, and it is called fast transient K channel because it is activated after about 1 ms of activation. 3. Calcium-activated K+ channel (KCa), which is double-gated by voltage and calcium. Its structure is slightly different, with two functionally unique areas, which are two-channel membranes. KCa is further divided into three categories: large conductance (BKCa), small conductance (SKCa), and intermediate conductance channels (IKCa). Each class can be divided into different subtypes, mainly IKCa1 in human lymphocytes and SKCa2 in Jurkat cells. SKCa3 is mainly found in B lymphocytes and mouse thymocytes. The inward rectifying K+ channel, the molecular structure of the inward rectifying K+ channel (Kir) was not clarified until 1993, consisting of two transmembrane helices and a H segment sandwiched between them, which is six transmembrane onepore, which is equivalent to Kv only. In the latter half of the molecule, it has no gate and voltage susceptor (H5) structure. In recent years, a new class of KATP channels (mito KATP) has been found on the mitochondrial membrane, and its classification can be attributed to Kir, which has not yet been determined. The basic molecular structure of the K+ channel includes the T1 tetrameric functional domain of the amino terminal cytoplasmic domain, the six transmembrane α-helical domains (S1-S6), the voltage-sensing domain (S1-S4), and the intercellular region (1P-loop) and a cytoplasmic carboxy-cytoplasmic domain. The K+ channel consists of a channel forming subunit (α-subunit superfamily) and an auxiliary subunit β. The auxiliary subunit β regulates the expression and distribution of the α-subunit, the kinetics and pharmacological properties of the channel opening-closing. The K+ channel forms the subunit KcsA (K+ channel of streptomyces), each subunit consists of two alpha helices spanning the cell membrane, and the two alpha helices are connected by a pore region, the pore helix and the selective filter consisting of approximately 30 amino acids. The inner helix of the two alpha helices faces the center of the ion channel, the short helix (P) and the inner helix (M2) form the inner wall of the channel, while the outer helix faces the lipid membrane. The inner spirals of the four subunits are close to each other in the membrane to form an inverted conical shape. The inner helix is inclined at a 25° angle with respect to the cell membrane and is slightly curved, so that the subunit is oriented like a “petal” toward the extracellular surface and close to the outer surface of the cell membrane. The subunit on the "petal" site contains the signal sequence of the K+ channel, forming an ion selective filtration zone. The K+ channel forming subunit consists mainly of four glycoproteins (subunits), mammalian K+ channel subunits associated with shake, which are Kv1 (Shaker), Kv2 (Shab), Kv 3 (Shaw), and Kv 4 (Shal) . However, the channel subunits are only one of them, and each subunit protein is translocated 6 times, named S1 ~ S6, and each channel has 4 such repeated components. The functional regions of the four repetitive components are linked and communicated. The human K+ channel S6 helix contains a conserved P-V-P motif, which acts as a hinge, like the TV-G-Y-G motif in KcsA. The N-terminus of the K+ channel molecule is related to the rapid “deactivation” of the K+ channel, which forms a spherical inactivating particle that blocks the inner port of the channel. This rapid inactivation is called N-type inactivation. The insertion of a 50-amino acid residue into the "strand" of the N-terminal inactive particle attached to the membrane delays the inactivation of the K+ channel. It is speculated that this is because the inactive particles cannot be found in the inner mouth of the K+ channel after the "chain" is lengthened. After the N-terminal inactivation of the particle mutation, the K+ channel is no longer inactivated. The mechanism by which the N-terminal shaker-type K+ channel is deactivated is very clear. It depends on the amino acid at the outer end of the S6 cell, which is called slow or C-type inactivation. There is also a T1 domain at the N-terminus, and some functional sequences are also found at the C-end. There are three N-linked glycosylation sites in the extracellular region and two cATP phosphorylation sites in the cytoplasmic region.

Potassium channel-related diseases and their mechanism

Potassium channels are a kind of protein complexes that exist on biofilms and have certain selective permeability to potassium ions. They can control the homeostasis of potassium ions inside and outside the cell membrane, regulate cell membrane potential, and participate in a series of physiological or pathophysiological processes. The current study found that abnormalities in potassium channels are the cause of many diseases such as arrhythmia, neuropsychiatric diseases, and tumors. Many experiments have confirmed that hyperproliferative tumor cells may be associated with potassium channels, and the degree of tumor type and malignancy are also related to potassium channels. Human malignant tumors, such as colon cancer, pancreatic cancer, prostate cancer, and melanoma, have found that IKCa channels are significantly increased. The use of IKCa channel-specific inhibitors can significantly slow the proliferation of tumor cells and the growth of tumor tissues. The mechanism by which potassium channel blockers inhibit tumor cell proliferation is mainly to inhibit the action potential of cell membrane and change the most basic physiological characteristics of cells; it may reduce the expression level of potassium channel-related proteins in tumor tissues. The increase or opening of potassium channels makes the cells hyperpolarized, which can lead to the opening of calcium channels activated by non-voltage-sensitive calcium release, allowing calcium ions to enter the cells, facilitating calcium-related signaling and causing tumors. Cell proliferation is accelerated, and potassium channel blockers can inhibit this process and inhibit tumor cell proliferation.

Reference:

  1. Leanza L, Venturini E, Kadow S, et al. Targeting a mitochondrial potassium channel to fight cancer. Cell Calcium. 2015, 58(1):131-138.
  2. Leanza L, O'Reilly P, Doyle A, et al. Correlation between potassium channel expression and sensitivity to drug-induced cell death in tumor cell lines. Current Pharmaceutical Design. 2014, 20(2):189-200.
  3. Kuang Q, Purhonen P, Hebert H. Structure of potassium channels. Cellular & Molecular Life Sciences. 2015, 72(19):3677-3693.

Laskowski M, Augustynek B, Kulawiak B, et al. What do we not know about mitochondrial potassium channels? Biochimica et biophysica acta. 2016, 1857(8):1247-1257.

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