Ion pores

Classification of P2 purinoceptors has been limited by a lack of potent, selective, and bioavailable antagonists. Nonetheless a rational scheme for P2 purinoceptor nomenclature divides P2 receptors into two superfamilies P2Y5 LGIC family having four subclasses and P2Y) a GPCR family having seven subclasses. A third receptor type, designated the P22) is a nonselective ion pore. 

The K+ channel is a tetrameric molecule with one ion pore in the interface between the four subunits... 

Figure 12.9 Schematic diagram of the stmc-ture of a potassium channel viewed perpendicular to the plane of the membrane. The molecule is tetrameric with a hole in the middle that forms the ion pore (purple). Each subunit forms two transmembrane helices, the inner and the outer helix. The pore heJix and loop regions build up the ion pore in combination with the inner helix. (Adapted from S.A. Doyle et al., Science 280 69-77, 1998.)...

The overall length of the ion pore is 45 A and its diameter varies along its length (Figure 12.11). As expected for a channel, there is a surplus of... 

Figure 12.11 Schematic diagram of the ion pore of the K+ channel. From the cytosolic side the pore begins as a water-filled channel that opens up into a water-filled cavity near the middle of the membrane. A narrow passage, the selectivity filter, links this cavity to the external solution. Three potassium ions (purple spheres) bind in the pore. The pore helices (red) are oriented such that their carboxyl end (with a negative dipole moment) is oriented towards the center of the cavity to provide a compensating dipole charge to the K ions. (Adapted from D.A. Doyle et al.. Science 280 69-77, 1998.)...

The ion pore has a narrow ion selectivity filter The bacterial photosynthetic reaction center is built up from four different polypeptide chains and many pigments The L, M, and H subunits have transmembrane a helices... 

Ca2+ Channel Blockers. Figure 1 Most voltage-gated Ca2+ channels exist as a hetero-oligomeric complex of several subunits, a 1 subunits form the Ca2+-selective ion pore and contain the voltage-sensors of the channel. 

Figure 2.1 Diagram of nicotinic acetylcholine receptor (nAChR) structure. A top view of (A) an a7 nAChR and (B) a p2 nAChR shows that homomeric and heteromeric classes of nAChRs are both pentameric in structure. Each subunit is made up of four transmembrane domains with the M2 domain making up the ion pore. (C) A side view of the four transmembrane regions shows the N terminus, C terminus, and large M3-M4 intracellular loop that make up each nAChR subunit. The extracellular loops are available for binding to ligands and the intracellular loop is available for regulation of the nAChR by intracellular signaling proteins.

Figure 2.2 Diagram of a voltage-activated sodium channel protein. The channel is composed of a long chain of amino acids intercormected by peptide bonds. The amino acids perform specific functions within the ion channel. The cylinders represent amino acid assemblies located within the membrane of the nerve cell and responsible for the foundation of the ion pore.

The transmembrane domains have different functions, according to the type of receptor. For ligand-controlled receptors, the function of the transmembrane domain is to pass the signal on to the cytosohc domain of the receptor. For hgand-controlled ion channels, the transmembrane portion forms an ion pore that allows selective passage of ions (see Chapter 16). 

An important transcriptional target of the p53 protein that can induce apoptosis is the bax gene. The Bax protein belongs to the family of Bcl-2 proteins (see 15.3.2) and has a proapototic effect. There is speculation that the p53-induced increase in Bax concentration leads to formation of ion pores in mitochondria and that cytochrome c is released into the cytosol via these pores. Cytochrome c then functions as a cofactor which, together with Apafl protein, activates procaspase 8 and initiates the apoptotic program. 

The dotted line indicates the location of the ion pore, a) Na channel b) Ca channel c) K channel. According to CatteraU, (1995) with permission. 

The large subunit is generally capable of forming an ion pore alone. In the large sub-imits of the Na and Ca charmels, four homologous domains can be identified that each have six potential transmembrane helices. The large subimit of the charmel has only one of these domains. Despite this, it fits into the structural principle of the Na and Ca channels since the large subunit is present as a tetramer. 

Fig. 16.12. Subunit structure of the acetylcholine receptor, a) The acetylcholine receptor has the subunit structure 02 7 - The four transmembrane elements Ml—M4 are shown for the y subunit. The binding sites for acetylcholine (ACh) are located on the a-subunits. b) It is assumed that the inner wall of the ion pore is formed by M2 helices of the five subunits, c) Postulated configuration of the M2 helices in the narrowest region of the ion channel. In the closed state, five leucine residues (one per subunit) lie in the ion channel and hinder passage of ions. Above and below the block, there are negatively charged residues that serve as prefilters for ion passage.

Membrane receptors may be involved directly in the cellular response to the drug by acting as an ion pore and thus changing the membrane permeability.61... 

Finally, there was a resurgence of interest in psychotogenic effects of ketamine in the early 1990s, following demonstrations that dissociative anesthetics such as PCP and ketamine induce their unique psychotomimetic effects by binding to a site located within the ion pore of the NMDA receptor (Anis et al., 1983 Javitt et al., 1987 Javitt and Zukin, 1991). Such studies remain ongoing and provide... 

Each sodium channel is composed of a large a subunit (-260 kDa) that forms the ion pore. The a subunits are pseudotetramer proteins, which contain four internally homologous domains (I-IV), each of which has six hydrophobic transmembrane helices and additional hydrophobic segments that contribute to the formation of the ion pore (Figure 7.5). 

Calcium channels are present in nerve terminals and muscles. They consist of four homologous domains arranged symmetrically around a central ion pore (Figure 7.11 and 712). Therefore, calcium and sodium channels share the basic structure of these repeat domains (I—IV). Under normal conditions, muscle contraction is mediated by calcium channels, as shown in the following text. Depolarization caused by an action potential in the motor nerve terminal activates calcium channels and triggers an influx of Ca2+ ions. These ions... 

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