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A. Description of Channelsnavigator

  1. Channels form holes or pores in membranes
  2. They are integral membrane proteins
    1. Typically 200-1000 amino acids for eukaryotic ion channels
    2. Peptide antibiotics which form pores such as gramicidin are 20 amino acids
    3. Most mammalian channels have multiple transmembrane domains
  3. Allow for various type sof communication
    1. Cell-cell communication through gap junctions (see below)
    2. Cell-outside communication
    3. Cell cytosol and organelles - including nuclear pores, mitochondria
  4. Summary of Structure and Function
    1. Form hole or pore in lipid membrane, traversing bilayer
    2. Allow for passage of millions of molecules (usually ions) per second
    3. Most channels are remarkably selective for specific ions
    4. Small molecular conformational changes allow gating of channels
    5. Gating is period opening and closing of channel
    6. Sudden opening of channel allows burst of current (picoAmpere levels)
    7. Gating leads to "square wave" function of single channels
    8. Net ion movements are curved waves due to summing of gated channel effects
  5. Major Organs with Ion Channels
    1. All organs have critical ion channels
    2. Excitable Tissue: Heart, Brain, Muscle
    3. Kidney - all tubular epithelia
    4. Pulmonary epithelia - trachea and bronchi
    5. Gastrointestinal epithelia
  6. Diseases due to mutations in channel genes are called "channelopathies"

B. Physics of Ion Channels
[Figure] "Ion Channels: Ohm's Law" navigator

  1. Potential Energy Stored as Chemical Gradient
    1. Cells utilize energy to initiate and maintain chemical gradients across membranes
    2. Up to 50% of a cell's total expenditure may be used in maintaining gradients
    3. When ions are distributed unequally across a membrane, they form a gradient
    4. These ion gradients are batteries, with stored potential energy (potential)
  2. The potential stored in the gradient (V) can be used to drive additional ion currents
    1. Ohm's Law: I (current, amperes) = G (conductance, siemens) x V (volts)
    2. G is the reciprocal of the resistance (R) of the system (usually in ohms)
    3. In reality, channels display a non-linear relationship between current and voltage
    4. Thus, the value of G changes for any particular voltage (G is a function of V)
    5. This change in G is called rectification
    6. Rectification can be inward or outward, depending on how G changes as a function of V
    7. Thus, G may be effectively 0 at some voltages, then increase above a threshhold level
    8. Current outward is taken as positive (for positive ions)
  3. Nernst Potential for an Ion
    [Figure] "Ion Channels: Ohm's Law"
    1. The point on the current-voltage curve where current=0 is the Nernst Potential (NP)
    2. The NP is the voltage where no current flows for that particular ion
    3. The NP is also where the ion current across the membrane reverses direction
    4. In equation format, V (volts) = (I/G) + NP
    5. NP is also called the reversal potential for an ion
  4. Reversal (Nernst) Potentials for some Ions
    1. These vary between cell types (channel types); common ranges are given
    2. Na+ ~ 70mV (sodium normally moves out)
    3. K+ -70 to -100 mV (potassium accumulates in cells)
    4. Cl- is -30 to -65 mV (chloride moves and out)
    5. Ca2+ is +150mV (calcium is sequestered and extracellular)
    6. Resting membrane voltage is around -80mV for many cell types
  5. Gating of Channels
    1. Gating (opening and closing) of channels allows for specific regulation
    2. Gating can be described by various parameters
    3. One important parameter is Po, the fraction of time (probability) a channel spends open
    4. Po therefore ranges from zero (always closed) to 1.0 (always open)
    5. G, the conductance, may be rewritten as: G = N x Po x g
    6. N is number of channels in membrane and g is the conductance of single channel
    7. These equations show how channel function can be modulated
  6. Modulation of Channel Function
    1. Changing the number (N) of channels in a membrane
    2. Alteration in the ionic conductance of single channel (g)
    3. Alterations in g or Po can occur in a number of ways including changing lipid membrane
    4. Phosphorylation and dephosphorylation can alter g or Po
    5. Interactions with other proteins, cytosolic factors, or cytoskeleton may alter Po (or g)
    6. Voltage changes in the cell can alter Po
  7. Common Gating Modifiers
    1. Voltage gated channels
    2. Intracellular molecules: as in calcium-activated channels
    3. Cyclic nucleotides: as in cGMP or cAMP activated channels
    4. G-protein gated channels
    5. Ligand gated channels
  8. A clear understanding of the chloride and other anion channels is not yet available

C. Overview of Ion Channel Structuresnavigator

  1. Majority of eukaryotic channels are multispan transmembrane proteins
  2. Most channels formed by multiple polypeptides (same or different subunits)
  3. Heteromeric Channels
    1. Voltage gated K+, Na+ and Ca2+ channels
    2. Major alpha subnit (can form simple pore in membranes)
    3. Other subunits form modulatory and/or regulatory functions
  4. Homomeric Channels
    1. CIC Chloride Channels
  5. Six Membrane Spanning Segments
    1. Voltage gated ion channels - major channels in nerve and muscle
    2. Cyclic nucleotide gated (CNG) cation channels
    3. Aquaporins
  6. Four Membrane Spanning Segments
    1. Majority of ligand gated channels fall into this class
    2. Nicotinic Acetylcholine Receptor
    3. Gama-aminobutyric acid (GABAa) Receptor
    4. Ionotropic Glycine Receptor
    5. Inhibitory Glutamate Receptor
    6. Serotonin Type 3 (5-HT3) Receptor
    7. Either anions (glycine, I-Glut, GABAa) or cations (nAChR, 5-HT3) are conducted
    8. Likely consist of five subunits, either homopentamers or heteropentamers
    9. Each alpha polypeptide has four membrane spanning alpha helices
  7. Two Membrane Spanning Segments
    1. Inwardly rectifying K+ channels
    2. ATP-sensitive K+ channels
    3. Amiloride-sensitive epithelial Na+ channels
    4. ATP-gated cation channels (P2X or Purinergic Receptors)

D. Summary of Voltage Gated Channels [11,20]navigator

  1. Major cation channels for excitation in nerve and muscle
  2. High selectivity for specific cations
  3. Each channel consists of 2 or more subunits alpha, beta, gamma or delta
    1. In general, the alpha subunit is the major pore structure protein
    2. alpha subunits contain alpha helical membrane spanning domains
    3. A total of 24 membrane spanning domains is found in all channels
    4. In K+ channel, this comes from 4 alpha polypeptides, each with one 6-membrane span
    5. In Na+ and Ca2+ channels, each alpha polypeptide has 4 domains of 6-membrane spans
  4. Open channels can conduct ions at rates near free diffusion limits
  5. Opening of channels is highly regulated
    1. Highly regulated opening and closing of channels dependent on voltage
    2. The alpha polypeptides are intrinsically voltage dependent for opening
    3. At non-permissive voltages, the channels are at rest
    4. Voltage changes induce conformational changes in channels, allowing them to open
    5. The beta, gamma, and/or delta subunits can alter the voltage dependent properties
  6. Inactivation
    1. Once open (at appropriate voltage), channels close in milliseconds to seconds
    2. This inactivation is believed to occur by channel plugging itself
    3. "Hinged-lid" and "ball on chain" mechanisms of plugging have been postulated
    4. beta, gamma and/or delta subunits can alter inactivation properties
  7. Major Ions and Membrane Potentials [11]
    1. Calcium - passive flux inward, current inward, depolarization
    2. Sodium - passive flux inward, current inward, depolarization
    3. Potassium - passive flux outward, current outward, repolarization
    4. Chloride - passive flux inward, current outward (negative charge), repolarization

E. Sodium (Na+) Channels [29]navigator

  1. Voltage Gated, Na+(V)
    1. Six membrane spanning domains
    2. alpha subunit has 4 domains of 6-membrane alpha helices
    3. Therefore, only one alpha subunit is required for single channel formation
    4. Selectivity for Na+ > 10 fold other ions
    5. Critical for normal cardiac and CNS functions
    6. Gating mechanisms are fairly well understood for Na+(V) channels
    7. Depending on gate conformation, Na+(V) exist in resting, active and inactive forms
    8. Mutations in Na+ channels found in various myotonias
  2. Gating [11]
    1. Two major gates, m and h, have been described for Na+(V) channels
    2. The gates exist in different parts of the same (alpha) channel polypeptide
    3. Structural motifs responsible for gating m (rapid) and h (slow) gates understood
    4. There are three phsiologic conformations for these gates
    5. These conformations correspond exactly to the forms of Na+(V) channels
    6. In the resting, net closed state, the m gate is closed and h gate is open
    7. The m gate opens rapidly on depolarization from the resting state
    8. The h gate, open in the resting state, begins to close on depolarization
    9. The inactive (closed) state has the m gate open and the h gate closed
    10. The refractory period is due to the closure of the h gate
    11. As repolarization occurs, the m gate closes and the h gate slowly opens
  3. Epithelial Na+ channels (amiloride sensitive)
    1. Non-voltage gated channels
    2. Found on apical membranes of many NaCl-absorbing epithelia
    3. Crucial for transepithelial salt trasport
    4. Blocked by the potassium sparing diuretic amiloride
    5. Bronchiolar epithelium and renal collecting duct contain major activities
    6. Renal channel is discussed below
    7. Mutations in epithelial sodium channel subunits can lead to blood pressure changes [21]
    8. Activating mutations in ß or gamma cause Liddle's syndrome (pseudoaldosteronism) [16]
    9. T594M mutationin ß-subunit are associated with hypertension in black women [18]
    10. Bronchiolar channels can be blocked with amiloride, useful in cystic fibrosis (CF)
    11. Mutant CF chloride channels lead to hyperexpression of these Na channels

F. Potassium (K+) Channels [27]navigator

  1. Summary of K+ Channels [11]
    1. Inwardly (Anomolous) Rectifying (IR) K+ channel (Kir)
    2. Outward (Delayed) Rectifier (Ko)
    3. Transient outward current (Ktr)
    4. Calcium activated K+ channel (Kca)
    5. Sodium activated K+ channel
    6. ATP sensitive K+ channels (Katp)
    7. Acetylcholine activated K+ channel
    8. Arachidonic acid-activated K+ channel
  2. Voltage Gated (Kv)
    1. Simplest of voltage-gated channels
    2. alpha subunit has six membrane spanning alpha helices
    3. Several different alpha subunits exist and can form homotetramers or heterodimers
    4. Four polypeptides are required for K+ channel
    5. ß-subunit is entirely cytosolic and alters voltage dependence of alpha subunits
  3. Inwardly Rectifying (IR) K+ Channel (Kir)
    1. Inward rectification means that inward flow of K+ is greater than outward flow at equal but opposite driving forces
    2. Some of the Kir channels are strongly rectifying, with little outward flow at all
    3. All have two-membrane spanning alpha helices with a loop between them
    4. IR caused by plugging internal mouth of channel
    5. Magnesium (Mg2+) is usual plugging molecule for weak IR channels
    6. Polyamines (spermine, spermidine, putrescine, cadaverine) and Mg2+ block strong IR
    7. Note that "normal" K+ ion flow is outward (see above), so this channel is "anomolous"
    8. HERG channel plays key role in repolarization, affects QTc interval and prolongation
  4. Outward (Delayed) Rectifying K+ Channel
    1. Channels open when the heart is depolarized
    2. Carry the heart's major depolarizing current
    3. Heterogeneity in these channels contributes to variations in action potential durations
    4. Dofetilide (Tikosyn®), an anti-arrhythmic, selectively blocks this channel [26]
  5. ATP sensitive K+ channels (Katp)
    1. Found in pancreatic ß-cells, involved in insulin secretion
    2. Epithelial ATP-regulated secretory cheannel (Kir1, ROMK), found in kidney
    3. Also found in muscle, heart, CNS
    4. Endothelial Katp and Kca critical for regulation of blood vessel diameter [31]
    5. May be involved in protection from cell death during ischemia
    6. Weak inward rectification, inhibition by intracellular ATP
    7. Nicorandil opens Katp leading to vasodilation, reduction of angina [34]
  6. Pancreatic ß-Cell Katp Channel
    1. Formed by association of Kir6.2 subunits with SUR1, another Kir protein
    2. SUR1 is the sulfonylurea receptor and modulates channel function
    3. Stoichiometry of SUR1 to Kir6.2 is not presently known
    4. SUR1 is a member of the ABC (ATP binding cassette) family of proteins (see below)
    5. Sulfonylureas bind SUR1, inhibit the Katp channel, and stimulate insulin secretion
    6. SUR1 is mutated is familial persistent hyperinsulinemic hypoglycemia of infancy
    7. Meglitinides bind and close these channels, mainly in presence of glucose [33]
  7. Acetylcholine activated K+ channel (Kach)
    1. Vagal stimulation can hyperpolarize resting cardiac cells
    2. Mediated through acetylcholine receptors, activates Gi and opens Kach
    3. This slows muscle firing and reduces heart rate
    4. Similar transduction cascade occurs with adenosine binding to purinergic receptors
    5. Channel consists of heterodimer with two inwardly rectifying K+ channel proteins
  8. Arachidonic acid-activated K+ channel (Kaa)
    1. Lipid activated potassium channels
    2. Fatty acids liberated in ischemic heart activate these receptors
    3. Result is shortened cardiac action potential due to more rapid repolarization
    4. Acidosis, which promotes K+ exit from cells, also shortens action potential
  9. Long QT Syndromes
    1. Cardiac Potassium channels linked to Romano-Ward Long QT syndrome [2,3]
    2. Homozygous mutations in KVLQT1 gene, modulates K+ channel
    3. This mutation is linked to Jervell and Lange-Nielsen Long QT Syndrome [4]
    4. The LQT2 Syndrome is a mutation in the HERG gene

G. Calcium (Ca2+) Channels [24,28] navigator

  1. Introduction
    1. Calcium ion fluxes play major roles in cell activation and death
    2. Calcium is absolutely required for all types of muscle contraction
    3. Calcium involved in protease activation ("capains")
    4. Calcium involved in transcriptional regulation through calmodulins and related proteins
    5. Calcium critical in many types of signal transduction as second and third messengers
    6. Reperfusion damage is calcium dependent
  2. Types of Channels
    1. Voltage Gated - multiple types of voltage dependent Ca channels (L-, N-, etc.)
    2. L-type - long acting (slowly inactivating) calcium channels (alpha-1a subunit)
    3. N-type - neuronal channels associated with pain (alpha-1b subunit)
    4. T-type - transient calcium channels (alpha 1g, 1h, or 1i subunits)
    5. P/Q-type - major expression is in brain (Perkinje tissues)
    6. Receptor operated Calcium channels - including IP3 / cGMP-gated channels
    7. Intracellular (sarcoplasmic) calcium release channel (ryanodine receptor)
    8. Ryanodine receptor on sarcoplasmic tubules interact with longitudinal tubule L channels
    9. Tetrodotoxin (TTX) sensitive calcium channel (I-Ca-TTX) also carries Na+ [28]
  3. Overview of Voltage Gated Ca2+ Channels [20,25]
    1. These Ca2+ channels have >1000 fold selectivity for Ca2+ over Na+ or K+
    2. Complex of 4 or 5 subunits including alpha-1, alpha-2, ß, gamma, and delta
    3. The large alpha-1 polypeptide has 4 domains of 6-membrane alpha helices (Ca2+ specificity)
    4. Therefore, only one alpha subunit is required for single channel formation
    5. ß subunits are entirely cytosolic
  4. L-Type
    1. Major component of transverse tubules in muscle
    2. Majority of available calcium blockers bind to L-type channels
    3. alpha1A - CAG repeats found in 3' end, polymorphic, no known links to disease
    4. alpha1C - splice variants are known to affect inactivation kinetics
    5. In addition, alpha1c splice variants affect activities of dihydropyridine calcium blockers
    6. Mutant L-type channels are found in hypokalemic periodic paralysis [5]
    7. L type channels are prevelant in cardiac muscle as well as SA and AV nodes
    8. L type channels are also prevalent in vascular smooth muscle
    9. Additional subunits of L channel are regulatory (a2/d, ß, and gamma subunits) [7]
    10. Dihydropyridines are the most potent blockers of these channels
  5. N-Type
    1. Involved in pain perception, pre-synaptic terminals
    2. Ziconotide (SNX-111) blocks N-type calcium channels and is active in severe pain [35]
  6. T-Type
    1. Transient type calcium channels
    2. Prevalent in vascular smooth muslce and in the SA node of the heart
    3. In SA node, these channels play a role in pacemaker activity
    4. In addition, these channels play a role in growth stimulation of cardiac cells
    5. Blocking these channels reduces heart rate (SA node) and blood pressure
    6. In addition, blocking channels may prevent cardiac hypertrophy and remodelling
    7. Mibefradil is a potent blocker of these channels (withdrawn from market)
  7. P/Q-Type [6]
    1. Brain specific forms, mainly Perkinje cells
    2. Gene CACNA1A codes the alpha-1a subunit of the P/Q-type channel
    3. Mutations in CACNA1A linked with several human diseases
    4. Familial hemiplegic migraine - with or without cerebellar signs [30]
    5. Episodic ataxia 2
    6. Spinocerebellar ataxia 6
    7. Antibodies to P/Q channels present in Lambert-Eaton myasthenia [5]
    8. Mutation in P/Q channel can cause absence seizures [32]
  8. Ryanodine Receptor (RyR) [7]
    1. Calcium is released through the sarcolemmal calcium release channel
    2. This channel binds ryanodine and has been called the ryanodine receptor (coded by Ryr 1)
    3. Several mutations in the ryanodine channel appear to cause malignant hyperthermia
    4. This channel is also called the calcium release channel
    5. Dantrolene, an antidote for malignant hyperthermia, causes closure of the channel
    6. Several different RyR genes have been clones (skeletal, cardiac, and non-muscle)
    7. Malignant hyperthermia is autosomal dominant disease manifesting with anesthesia
  9. Inositol Triphosphate (IP3) Receptor
    1. IP3 binds to intracellular receptors and intiates calcium influxes
    2. There are several variants of the IP3 receptors, often coexpressed in tissues
  10. Miscellaneous Effects
    1. Amlodipine may have protective effects in viral myocarditis by blocking nitric oxide [8]
    2. Mibefradil may have protective effects in viral myocarditis and stroke

H. Cyclic Nucleotide Gated Channelsnavigator

  1. Cyclic GMP (cGMP) appears to be the major regulator for these channels
  2. Key Organ Systems
    1. Sight - retinal rod and outer cone segments
    2. Smell - olfactory receptors
    3. Kidney
    4. Cardiac - pacemaker activity in sinoatrial (SA) node
  3. Majority of cGMP gated channels are nonselective for cations, but do prefer Ca2+
  4. Composed of heteromultimers of alpha and ß subunits
    1. alpha subunits have 6-membrane spanning alpha helices similar to K+ channels
    2. alpha subunits have intrinsic channel forming function
    3. ß subunits modulate alpha function
    4. Stoichiometry of alpha and ß subunits is not known
  5. Cystic fibrosis chloride channel (CFTR) is also regulated by cAMP and protein kinase A

I. Chloride (Anion) Channelsnavigator

  1. Major role is to help stabilize resting membrane potential
  2. This is because the Nernst Potential for Cl- is close to that of resting cells
  3. Structural Classes
    1. Ligand gated: Glycine and GABAa Receptors
    2. Voltage gated: CIC gene family
    3. CFTR: cystic fibrosis transmembrane conductance regulator (~7pS conductance)
    4. Outwardly Rectifying Anion Channels
    5. Calcium activated chloride channels (~20pS conductance)
  4. CIC Gene Family
    1. Nine different members have been found in mammals
    2. These are designated CIC-1 to CIC-7, CIC-Ka and CIC-Kb
    3. CIC-2, CIC-6 and CIC-7 are found ubiquitously
    4. CIC-1 - skeletal muscle
    5. CIC-3, -4, -5, CIC-Ka and CIC-Kb in kidney
    6. Channels are 90-100K, with about 1000 amino acids
    7. Mutations in CIC-1 cause various inherited myotonias
  5. Outwardly Rectifying Anion Channels
    1. Involved in cell volume regulation, both swelling and shrinkage
    2. Channels are activated on cell swelling
    3. Mediate efflux of anions after cell swelling
    4. I(Cln) or ORCC is the major cloned outwardly rectifying anion (chloride) channel
  6. ORCC
    1. Outwardly rectifying chloride channel
    2. Variable conductance of chloride as a function of transmembrane voltages
    3. I(Cln) contains 4 ß-strands similar to those found in bacterial porins
    4. I(Cln) may be actual structural protein for the channel as a homodimer
    5. Mitochondrial voltage-dependent ion channel has similar structure
    6. ORCC conductance of chloride is modulated by CFTR

J. Water Channels (Aquaporins) navigator

  1. Found mainly in erythrocytes and in apical membranes of kidney collecting ducts
  2. Permit very high water permeability
  3. Six different aquaporin genes, AQP0 to AQP5, have been identified
    1. APQ0 found in the lens
    2. APQ1 is erythrocyte water channel
    3. Many of the aquaporins are found in kidney
    4. Inactivating mutations in AQP2 lead to one form of nephrogenic diabetes insipidus
    5. Therefore, AQP2 is ligand sensitive for antidiuretic hormone (ADH, vaspopressin)
  4. Structure is unlike the ion channels previously described
    1. Appear to be homotetramers, with each polypeptide having 6-membrane spans
    2. However, the polypeptides are folded into 2 domains of 3 transmembrane segments

K. Gap Junctionsnavigator

  1. Allow direct transfer of small molecules and ionic currents between cells
  2. Each cell contributes half of the gap junction
  3. Gap junctions are composed of oligomeric assembly of connexons
    1. Connexons consist of hemxamer of integral membrane proteins called connexins
    2. There are >11 different types of connexins
    3. These connexins have tissue specificity and transport specificity
  4. Common Tissues
    1. Glial Cells
    2. Epithelial Cells
    3. Smooth muscle cells
    4. Cardiac muscle cells
    5. Very rare in mammalian neurons
  5. Pathology of Gap Junctions
    1. Connexin-26 mutations associated with sensorineural hearing loss [3]
    2. Connexin-32 mutations associated with X-linked Charcot Marie Tooth neuropathy [4]

L. Renal Tubule Channels
[Figure] "Renal Tubular Cells" navigator

  1. Renal Collecting Duct Na+ Channel
    1. Found mainly in apical membranes of principal cells of collecting duct
    2. Provides Na+ entry for aldosterone regulated Na+/K+ pump use (basolateral membrane)
    3. This renal channel has alpha, ß, and gamma subunits
    4. Each polypeptide has two membrane spanning alpha-helices with large loop between each
    5. alpha subunits have intrinsic pore-forming activities
    6. Gamma and ß subunits modulate activity and increase currents
    7. Mutations found in channel cause various clinical syndromes [16,18]
  2. Glucose Transporter
  3. Proton Transporter
  4. H+/K+ Antiporter
  5. HCO3-/Cl- Antiporter
  6. Potassium (K+) Channel (apical)
    [Figure] "Renal TAL Cell"
  7. K+ Pump
  8. Na+/K+ Antiporter - ATP dependent (basal side)
  9. Na+/K+/2Cl- loop diuretic sensitive cotransporter (lumenal side)
  10. Water Transporters (aquaporin channels)

N. ABC Protein Familynavigator

  1. ATP binding casette (ABC) family
  2. SUR1 protein
    1. Sulfonylurea receptor
    2. Part of Kir from pancreatic ß-cells (see above)
  3. CFTR [14,19]
    1. Chloride channel, mutated in CF
      [Figure] "CF Ion Transport Defect"
    2. Always plays regulatory role (CF transmembrane conductance regulat
  4. P-Glycoproteins (Pgp-1)
    1. MDR1 gene, codes for enzyme which pumps out small molecule toxins
    2. Mediates resistance to various chemotherapeutic agents
    3. Related proteins include mrp1, others
  5. ALD Protein
    1. Mutations found in patients with peroxisome biogenesis
    2. Likely exists as functional homodimer
    3. Mutated in adrenoleukodystrophy
  6. PMP-70 Protein
    1. Mutations in patients with lipid disorders, Zellweger Syndrome
    2. Likely exists as functional homodimer
  7. Of the ABC proteins, only CFTR is clearly an ion channel

O. Gastrointestinal Transporters (incomplete listing)navigator

  1. Gastric H+/K+ Antiporter
  2. Small Intestinal Transporters (mainly absorption)
  3. Colonic Transporters (mainly secretion)
  4. Congenital Chloridorrhea [15]
    1. Chronic diarrhea beginning as infants
    2. Autosomal recessive trait due to inability to reabsorb chloride in GI tract
    3. Defect in ileal and colonic chloride-bicarbonate exchange transporter
    4. Moderate to severe hypokalemia and hypomagnesemia
    5. Blood hypochloremia (non-anion gap metabolic alkalosis)
    6. Low urinary chloride excretion
    7. Treatment: Oral sodium and potassium chloride, IV fluids
    8. Proton-pump inhibitors are effective and reduce gastric chloride secretion and diarrhea
  5. Duodenal Metal Transporters
    1. DMT-1 (same as NRAMP-2) protein is a membrane transporter protein
    2. DMT-1 increases absorption of iron and other divalent metal cations
    3. DMT-1 transport is an active, hydrogen-coupled system
    4. DMT-1 transport is located on the apical (luminal) side of duodenal mucosa
    5. DMT-1 mRNA levels are elevated in patients with hereditary hemochromatosis
  6. Sodium-linked glucose transporter (intestine, kidney) [23]

P. Ligand-Sensitive Channelsnavigator

  1. Purinergic Receptors (P2X, ATP-gated Cation Channels)
    1. Activated by extracellular ATP
    2. Found on neurons and a large number of other cells
    3. ATP likely acts as a neurotransmitter at some nerve-nerve and nerve-muscle junctions
    4. May play role in pain sensation
    5. At least 7 P2X receptors are now known
    6. Two-membrane spanning segments; each with two alpha helices
    7. Between the two alpha helices is a large, glycosylated extracellular loop
  2. GABA-Receptors
    1. Major inhibitory neurotransmitter in brain
    2. Multiple subtypes of GABA-R are known
    3. Conduct anions
    4. Targets for many epileptic agents

References navigator

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  12. Splawski I, Timothy KW, Vincent GM, et al. 1997. NEJM. 336(22):1562 abstract
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