Ion Channels
Definition
Ion channels are membrane protein complexes and their function is to facilitate the diffusion of ions across biological membranes.
Discovery
British biophysicists Alan Hodgkin and Andrew Huxley hypothesized the existence of ion channels as a part of their Nobel Prize-winning theory of the nerve impulse, published in 1952. Existence of channel was confirmed in the 1970's with an electrical recording technique known as the "patch clamp," by Erwin Neher and Bert Sakmann, the technique's inventors 1. 2003 Nobel Laureates Peter Agre and Roderick MacKinnon, have analysed the physico-chemical properties of ion channel functions, all of which are needed for the cell to function .
Structural Characteristics
In 1990s the first structure of an ion channel solved at atomic resolution .3nm is that of the bacterial porins, a family of homo-trimeric channel proteins. Each subunit contains 16 to 18 transmembrane, anti-parallel beta-strands forming a beta-barrel structure. The beta-strands are amphipathic, they contain alternating polar and non-polar residues and the inter-strand interaction is fully saturated with H-bonding. This creates a hydrophilic pore interior providing a water filled channel. The channel has a large diameter of 0.8x1.1nm, and is non-selective for small ions. However, it has an upper exclusion size limit corresponding to molecular weights of about .6 K Da. Most metabolites have molecular weights lower than .6 KDa and have been shown to pass through porin channels .
Mode of Action
An ion channel is an integral membrane protein or more typically an assembly of several proteins. Such "multi-subunit" assemblies usually involve a circular arrangement of identical or related proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer. While large-pore channels permit the passage of ions more or less indiscriminately, the archetypal channel pore is just one or two atoms wide at its narrowest point, it conducts a specific species of ion, such as sodium or potassium, and conveys them through the membrane single file--nearly as fast as the ions move through free fluid. Access to the pore is governed by "gates," which may be opened or closed by chemical or electrical signals, or mechanical force, depending on the variety of channel. There are different groups of channels,
- Ligand gated channels neurotransmitters
- Voltage gated channels transmembrane potential (electric field)
- Second messenger gated channels nucleotides, G-proteins
- Mechanosensitive channels osmotic pressure, membrane curvature
- Gap junctions, porins not gated
X-ray analysis potassium channel from Streptomyces lividans(called K1) reveals that four identical subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12? long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main chain carbonyl oxygen atoms from the K1 channel signature sequence line the selectivity filter, which is held open by structural constraints to coordinate K1 ions but not smaller Na1 ions. The selectivity filter contains two K1 ions about 7.5 angstroms apart. This configuration promotes ion conduction by exploiting electrostatic repulsive forces to overcome attractive forces between K1 ions and the selectivity filter. The architecture of the pore establishes the physical principles underlying selective K1 conduction 2.
Functions
Role in nervous systems, channels are especially prominent components of the nervous system, "voltage-gated" channels conduct the nerve impulse and "transmitter-gated" channels mediate conduction across the synapses. Many toxins usually act on channels for shutting down the nervous systems of predators and prey 3.
Biological role, ion channels figure in a wide variety of biological processes that involve rapid changes in cells, such as cardiac, skeletal, and smooth muscle contraction, epithelial transport of nutrients and ions, T-cell activation and pancreatic beta-cell insulin release 4.
Drug targets, ion channels are the main targets of many drugs already used in the clinics. Most of these drugs were introduced in therapy based on the experience acquired quite empirically, and many were discovered afterward to target ion channels. Intense research is being conducted to develop new drugs acting selectively onion channel subtypes and aimed at the understanding of the intimate drug-channel interaction. Polymorphisms or mutations in ion channel genes modify sensitivity to drugs, opening the way toward the development of pharmacogenetics 5.
References
1.Book: Neuroscience, Ion Channels Underlying Action Potentials., by Dale P, George A, Sunderland (MA): Sinauer Associates, Inc.; 2001
2.Doyle DA, Morais CJ, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998). The structure of the potassium channel: molecular basis of K conduction and selectivity. Science, 280(5360):69-77.
3.Camerino DC, Tricarico D, Desaphy JF (2007). Ion channel pharmacology. Neurotherapeutics, 4(2):184-98.
4.Book: Chapter 6: Electrical Excitability and Ion Channels.by Basic neurochemistry: molecular, cellular, and medical aspects., by Hille B, Catterall WA. Philadelphia: Lippincott-Raven.
5.Camerino DC, Desaphy JF, Tricarico D, Pierno S, Liantonio A (2008). Therapeutic approaches to ion channel diseases. Adv. Genet., 64:81-145.
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Ion channels are membrane protein complexes and their function is to facilitate the diffusion of ions across biological membranes.
Discovery
British biophysicists Alan Hodgkin and Andrew Huxley hypothesized the existence of ion channels as a part of their Nobel Prize-winning theory of the nerve impulse, published in 1952. Existence of channel was confirmed in the 1970's with an electrical recording technique known as the "patch clamp," by Erwin Neher and Bert Sakmann, the technique's inventors 1. 2003 Nobel Laureates Peter Agre and Roderick MacKinnon, have analysed the physico-chemical properties of ion channel functions, all of which are needed for the cell to function .
Structural Characteristics
In 1990s the first structure of an ion channel solved at atomic resolution .3nm is that of the bacterial porins, a family of homo-trimeric channel proteins. Each subunit contains 16 to 18 transmembrane, anti-parallel beta-strands forming a beta-barrel structure. The beta-strands are amphipathic, they contain alternating polar and non-polar residues and the inter-strand interaction is fully saturated with H-bonding. This creates a hydrophilic pore interior providing a water filled channel. The channel has a large diameter of 0.8x1.1nm, and is non-selective for small ions. However, it has an upper exclusion size limit corresponding to molecular weights of about .6 K Da. Most metabolites have molecular weights lower than .6 KDa and have been shown to pass through porin channels .
Mode of Action
An ion channel is an integral membrane protein or more typically an assembly of several proteins. Such "multi-subunit" assemblies usually involve a circular arrangement of identical or related proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer. While large-pore channels permit the passage of ions more or less indiscriminately, the archetypal channel pore is just one or two atoms wide at its narrowest point, it conducts a specific species of ion, such as sodium or potassium, and conveys them through the membrane single file--nearly as fast as the ions move through free fluid. Access to the pore is governed by "gates," which may be opened or closed by chemical or electrical signals, or mechanical force, depending on the variety of channel. There are different groups of channels,
- Ligand gated channels neurotransmitters
- Voltage gated channels transmembrane potential (electric field)
- Second messenger gated channels nucleotides, G-proteins
- Mechanosensitive channels osmotic pressure, membrane curvature
- Gap junctions, porins not gated
X-ray analysis potassium channel from Streptomyces lividans(called K1) reveals that four identical subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12? long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main chain carbonyl oxygen atoms from the K1 channel signature sequence line the selectivity filter, which is held open by structural constraints to coordinate K1 ions but not smaller Na1 ions. The selectivity filter contains two K1 ions about 7.5 angstroms apart. This configuration promotes ion conduction by exploiting electrostatic repulsive forces to overcome attractive forces between K1 ions and the selectivity filter. The architecture of the pore establishes the physical principles underlying selective K1 conduction 2.
Functions
Role in nervous systems, channels are especially prominent components of the nervous system, "voltage-gated" channels conduct the nerve impulse and "transmitter-gated" channels mediate conduction across the synapses. Many toxins usually act on channels for shutting down the nervous systems of predators and prey 3.
Biological role, ion channels figure in a wide variety of biological processes that involve rapid changes in cells, such as cardiac, skeletal, and smooth muscle contraction, epithelial transport of nutrients and ions, T-cell activation and pancreatic beta-cell insulin release 4.
Drug targets, ion channels are the main targets of many drugs already used in the clinics. Most of these drugs were introduced in therapy based on the experience acquired quite empirically, and many were discovered afterward to target ion channels. Intense research is being conducted to develop new drugs acting selectively onion channel subtypes and aimed at the understanding of the intimate drug-channel interaction. Polymorphisms or mutations in ion channel genes modify sensitivity to drugs, opening the way toward the development of pharmacogenetics 5.
References
1.Book: Neuroscience, Ion Channels Underlying Action Potentials., by Dale P, George A, Sunderland (MA): Sinauer Associates, Inc.; 2001
2.Doyle DA, Morais CJ, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998). The structure of the potassium channel: molecular basis of K conduction and selectivity. Science, 280(5360):69-77.
3.Camerino DC, Tricarico D, Desaphy JF (2007). Ion channel pharmacology. Neurotherapeutics, 4(2):184-98.
4.Book: Chapter 6: Electrical Excitability and Ion Channels.by Basic neurochemistry: molecular, cellular, and medical aspects., by Hille B, Catterall WA. Philadelphia: Lippincott-Raven.
5.Camerino DC, Desaphy JF, Tricarico D, Pierno S, Liantonio A (2008). Therapeutic approaches to ion channel diseases. Adv. Genet., 64:81-145.
Please visit our Blog on Blogspot Bio-Synthesis
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Founded in 1984, Bio-Synthesis, Inc. was first known as OCS Laboratories. It was the first producer of commercially available synthetic DNA and, in 1985, became a producer of synthetic peptides. In 1989, OCS incorporated as Bio-Synthesis, Inc. and moved its laboratories to Lewisville, Texas. Today, BSI occupies 10,000 square feet of modern laboratory space (completed in 1995) located 20 miles from downtown Dallas and 10 miles from D/FW airport. Among the surrounding academic institutions are: University of Texas Southwestern Medical School (12 miles), University of North Texas (10 miles), and University of North Texas Health Science Center (25 miles). These universities provide excellent library resources. Since its inception, BSI has steadily expanded its product lines and services to meet the growing needs of the molecular biology community. It has maintained its position as an aggressive, innovative company in a highly competitive marketplace without sacrificing quality. In the beginning, our primary emphasis was on synthesizing high quality DNA primers and linkers, which were the initial uses of oligos. Today, newer technologies, such as gene construction, PCR, mutagenesis, combinatorial libraries, dye/adduct labeling, DNA microarrays, peptide-nucleic acid chimeras, etc. have challenged the molecular biology field. In response, BSI has branched into several related areas including DNA paternity testing, DNA HLA typing, PNA synthesis, genomic sequencing, fluorescence-based genotyping, custom organic synthesis and other molecular biology based applications.
The Research and Development Division comprises a number of Ph.D. and M.D. professionals with backgrounds in molecular biology, immunology, nucleic acids, peptide synthesis, general organic chemistry, and automated amino acid sequencing. The Molecular Biology Division is set up to handle most modern experimental procedures; the Immunology Division specializes in immunodiagnostic-based reagents.
Not only has BSI continued to provide quality DNA products and services for the research community, but it has also become a world leader in providing custom peptide products and services. Using state-of-the-art solid phase peptide chemistries, BSI provides high quality custom peptides, performs carrier conjugations, antipeptide antibody production, antigenic peptide design, synthesis of long and/or modified peptides, MALDI TOF analysis, contract research, consultation services and more.
Biomedical researchers worldwide in universities, biotech companies, private clinics, and government agencies use products from Bio-Synthesis, Inc. in studies ranging from PCR diagnostics to cancer research and the Human Genome Project. Contact us to discover how BSI can customize products/services to suit your research requirements.
For more detail please visit our About Us
Please Contact Us :
Address: 612 E. Main street
City: Lewisville
State: Texas
Country: USA
Postal Code: 75057
Phone Number: 972-420-8505
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BSI is a U.S. based company whose primary emphasis is on the synthesis of high quality custom products for a variety of applications and a full-service contract manufacturing organization (CMO) delivering research, development and production services for cGMP clinical batch manufacturing.
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BIO-SYNTHESIS, INC., is a leading life science products company with over 20 years of experience in the design and synthesis of Custom Peptide, small molecules and reagents for small scale research and bulk pharmaceutical trials. Using state of the art technology in our well-equipped laboratories.
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