Ion channels are a superfamily of integral membrane proteins that are capable of controlling the voltage gradient across the membrane of living cells by regulating selective ion conduction. The function of an ion channel can be activated by the binding of a specific ligand or a change in the transmembrane potential. These two superfamilies are named ligand-gated ion channels (LGICs) and voltage-gated ion channels (VGICs) respectively. In addition to these, the ion channels can also be gated by light, second messengers or other sources. LGICs and VGICs are the two most studied superfamilies of ion channels. Generally a certain ion channel allows passing only one specific type of ion, such as a proton, sodium, potassium, calcium or chloride. Genetic disorders affecting ion channels can cause many diseases, known as channelopathy diseases. Understanding the mechanism of ion channel actions is significant for developing more effective pharmaceutical and diagnostic techniques.
LGICs are also known as ionotropic receptors. They are typically composed of five subunits arranged surrounding an ion-conducting pore. The channel undergoes conformational changes, from closed to open, upon the binding of ligands. LGICs include nicotinic acetylcholine receptors (nAChRs), Y-aminobutyric acid type A receptors (GABAA), glycine receptors and serotonin 5-HT3 receptors. nAChRs and serotonin 5-HT3 receptors conduct cations (sodium and potassium) while GABAA and glycine receptors are chloride channels. Most LGICs are the targets which anesthetic agents have their effects on. nAChRs have been considered the prototypical representatives of LGICs. A nAChR contains three domains classified by their locations with respect to the membrane: an extracellular ligand-binding domain, a membrane-spanning pore and an intracellular domain. The extracellular ligand-binding domain contains two acetylcholine binding sites and it shapes a long vestibule for ions. The pore domain in each subunit consists of a bundle of four helices (M1-M4). When both binding sites in the extracellular domain are occupied by acetylcholine, the pore domain opens and allows ions to pass through the membrane. The intracellular domain shapes a smaller vestibule which has a narrow lateral opening for the ions. The structure of a nAChR was reported by Unwin in 2005.
VGICs also share a common structural motif. They are composed of either four identical subunits in the case of potassium channels (Kv channels) or homologous domains in the case of sodium and calcium channels. The four subunits (or domains) associate (or are linked) to form the channel with the pore spanning the membrane. Kv channels are the most studied family of VGICs. They exist widely in excitable cells, such as neurons and cardiac muscle cells, and play a major role in repolarizing the action potentials and modulating the frequency of these potentials. Kv channels have been divided into 12 subfamilies (Kv1-Kv12) according to their relative sequence homology. The channels within each subfamily display over 65% sequence identity. Kv channels were originally less well characterized at the molecular level, as compared to voltage- gated sodium channels and calcium channels, until the gene encoding the sequence of the shaker K+ channel was discovered. In 2003, the crystal structure of the Kv channel from Aeropyrum pernix (KvAP) was reported, which was the first elucidation of the detailed atomic structure of a potassium channel. MacKinnon et al. also proposed a new model of how the voltage change was sensed by Kv channels. Briefly, the six segments (S1-S6) within one subunit of a Kv channel are divided into two groups. The S1-S4 segments comprise the voltage-sensitive domain (VSD) and the S5-S6 segments from each subunit form the pore domain (PD). The VSD, responsible for sensing the voltage changes, are arranged around the periphery of the PD. The movements of the VSD modulate the opening and closing of the PD. Although the crystal structure provides the architecture of a Kv channel, it fails to resolve the outstanding questions regarding the voltage-sensing mechanism.
Potassium ion channel
Potassium ion channels are membrane-spanning proteins that catalyze the rapid and selective transport of potassium ions (K+) across cell membranes. Selectivity refers to the fact that most ion channels only allow certain types of ions to pass through. In the case of the potassium ion channel, only potassium ions are allowed to pass through the cell membrane.
Potassium ion channels are needed because they help regulate a variety of processes. Potassium channels are involved in a wide range of physiological processes such as cardiac function and hormone regulation. Many different cellular signals can cause the potassium ion channel to open and close. This is referred to as gating, and give rise to the diversity of processes it’s involved in. The potassium ion channel can pass ions at near diffusion-limited rates (108 ions per second) and can precisely select against abundant and similar Na+. These properties have given rise to a great deal of interest in examining its structure in order to explain its function at the molecular level.
Study of the molecular structure of the potassium ion channel has been possible through advances in X-ray crystallography. Data from x-ray analyses have revealed that the potassium ion channel consists of four identical subunits that form a cone-like structure containing a central channel. Potassium ions travel in one direction through this channel. The direction the ions travel is from the intracellular space to the extracellular space (i.e., from inside the cell to the outside the cell). The portion of the protein nearest the extracellular space contains a special feature, which only allows potassium ions to pass into the extracellular space. This special feature is known as the selectivity filter and resides near the outer end of the channel.