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ION CHANNELS
     All living organisms require membrane ion channels.  In prokaryotes, such as those in the image below, 76 families of membrane transporters are known including 4 families of ion channel proteins, 4 families of primary ion transporters, and 54 families of secondary transporters (Paulsen, 2000). ARCHEBACTERIA

  Voltage regulated ion channels probably exist in all living organisms (Anderson, 2001).   The many kinds of ion channels are homologous.     Potassium channels (shaker family), hyperpolarization-activated cyclic nucleotide-gated channels (HCN), cyclic nucleotide-gated channels (CNG), polycystin (PKD) channels, and TRP receptors (homologous to the transient receptor potential channel protein in flies) all have homologous structures (Harteneck, 2000; Sorrentino, 2000). 

     The structure of the ancestral ion channel seems to have been a small protein with two transmembrane regions on either side of a pore-forming region.  This is the structure of the protein in many prokaryotic channels and eukaryotic inward rectifier channels.  Before the split between prokaryotes and eukaryotes, four additional transmembrane regions were added to an ancestral channel, producing a protein with a pore-forming region and 6 transmembrane regions.  Some prokaryotic channels and most eukaryotic channels possess this structure.  Some channels resulted from a fusion of a 6 transmembrane segment channel and a 2 transmembrane segment channel (Anderson, 2001).  Most potassium channels are formed by the interaction of four separate subunits composed of 6 transmembrane regions.  All sodium and calcium channels are formed by a single protein which is formed by four tandem regions composed of 6 transmembrane regions (Anderson, 2001).  Single amino acid substitutions can change the specificity of the ion channel from sodium to calcium (Plummer, 1999).

 

POTASSIUM CHANNELS

     Potassium channels are ancient proteins, and are conserved between archaea and eukaryotes (Jiang, 2002a and 2002b). Potassium channels are produced by α and β subunits.  The largest group of α channels are the voltage regulated channels and the α subunit core is conserved in both prokaryotes and eukaryotes (Biggin, 2000).  Eukaryotic channels retain their function when the eukaryotic channel pore is replaced by the pore from prokaryotic channels (Lu, 2001).  Voltage gated potassium channels represent the prototypical channel of the family of voltage regulated channels.  The simplest channels form tetramers using four subunits of the same gene. (Yellen, 2002; Fleishman, 2004).  As pictured below, the potassium channel is not only the simplest of the voltage regulated ion channels, its 6-transmembrane region structure (with the fourth unit being the voltage-regulated portion) is the prototype for the more complex sodium and calcium channels which are composed of four separate homologous regions.  The potassium, sodium, and calcium voltage regulated channels are pictured below (after Darnell, p.782). 


 

POTASSIUM CHANNEL
CHANNELS

     Multiple potassium channels are typical of animals, even cnidarians (Anderson, 2001).  Although adults of the nematode C. elegans possess 302 neurons, there more than 100 potassium channels known, more than in flies or vertebrates.  Many of these unique channels which are only expressed in a few cells (Salkoff, 2001; Biggin, 2000).

     There are more than 70 potassium channel genes known from mammals, about a dozen of which belong to a family of “background channels” which have 4 transmembrane segments and 2  domains in each subunit.  These channels are always open and function in determining the membrane potential.  Some neurons depolarize by inhibiting these channels.  In humans, these subunits include TALK-1, TALK-2, hTHIK-2, TASK-1, TASK-2, TREK-1, TREK-2, and TRAAK (Girard, 2001).

EPITHELIA

VOLTAGE REGULATED

     Voltage regulated potassium channels are components of every eukaryotic cell (such as those of a worm pictured above). 

 

Shaker-Related Family (named after the Shaker gene of Drosophila)

KCNA1 is part of a cluster on chromosome 12 which contains KCNA6 and KCNA5 genes.  Mutations in KCNA1 cause episodic ataxia.

 

KCNA2

 

KCNA3 is involved in T lymphocyte activation and proliferation.

 

KCNA4 is expressed in the heart and may affect the length of cardiac action potentials.

 

KCNA5

 

KCNA6 is expressed in the brain (cerebrum pictured below).

NEURON

KCNA7 is expressed in the heart and mutations may be a factor in heart blocks.

 

KCNA10 is regulated by cGMP.

 

KCNAB1, KCNAB2, and KCNAB3 are genes for the beta subunits of the Shaker channel.  These subunits do not possess pores for potassium but rather regulate the activity of the alpha subunits.

 

 

SHAB Homologue

    Shab is one of 3 potassium channels in Drosophila which are homologous to Shaker.

KCNB1

 

SHAW Homologue

     Shaw is one of 3 potassium channels in Drosophila which are homologous to Shaker. 

KCNC1 maps to the same chromosomal region as prolonged QT syndrome. 

 

KCNC2


KCNC3

 

KCNC4

 

SHAL Homologue

Shal is one of 3 potassium channels in Drosophila which are homologous to Shaker.

KCND1 is expressed in all tissues.  In the brain, the highest expression occurs in the cerebellum (pictu

NEURONS

KCND2 has several alternate transcripts, one of which is only expressed in the brain.

 

KCND3 is most highly expressed in the brain and heart.

 

E SUBFAMILY; voltage regulated

KCNE1 mutations are involved in Long QT syndrome affecting the cardiac cycle, Jervell Syndrome and Lange-Nielson Syndrome which affect the cardiac cycle and can include hearing loss.

 

KCNE2 mutations cause long QT syndrome and heart arrhythmias.  Cardiac muscle is pictured below.

CARDIAC

KCNE3 is expressed in skeletal muscle and mutations cause hyperkalemic periodic paralysis.

 

KCNEL1 is expressed in adult muscle, the central nervous system, and the placenta (pictured below); it is also expressed in migrating neural crest cells and somites of embryos.

PLACENTA

KCNF1 is a voltage regulated potassium channel which is expressed throughout the body and has its highest expression in the heart.  One transcript is present only in the brain.

 

G SUBFAMILY; Voltage Regulated

KCNG1 is expressed in the brain, placenta, kidney, and pancreas.

 

KCNG2 is expressed in the heart.

 

H SUBFAMILY; Voltage Regulated; Homologs of ether a go-go mutant in Drosophila

KCNH1

 

KCNH2 is involved in the cardiac cycle and suppresses extra heart beats.  Mutations causeLong QT syndrome, and Torsade de pointes (which can lead to ventricular fibrillation)

 

KCNH3 is expressed throughout the brain (cerebrum pictured below).

NEURON

KCNH4 is primarily expressed in the striatum.

 

KCNH5 has alternate transcripts, one of which is expressed only in the brain.

 

S SUBFAMILY; voltage Regulated

KCNS1 is expressed most highly in the olfactory bulb, cerebrum, hippocampus, amygdala, cerebellum, retina, and spinal cord.  Spinal cord neurons are pictured below.

NEURON

 

KCNS2 does not function as a potassium channel but can regulate the activity of other channels.

 

KCNS3

 

INWARD RECTIFYING POTASSIUM CHANNELS

J SUBFAMILY

KCNJ1 is expressed in the ascending loop of Henle and the distal nephron (nephron tubules of turtles are pictured below) where it affects salt reabsorption and blood pressure.  Mutations cause Bartter syndrome and Anderson syndrome whose symptoms may include low blood pressure, hypokalemic alkalosis, and salt wasting.

KIDNEY

KCNJ2 is expressed in the brain, heart, lung, skeletal muscle, and placenta.  Mutations cause Long QT syndrome.

 

KCNJ3 is most highly expressed in the heart and brain.

 

KCNJ4

 

KCNJ5 is expressed in the heart and is ATP sensitive.

 

KCNJ6 is expressed in the cerebellum, substantia nigra, and testes.  Neurotransmitter receptors may be coupled to these channels.  Mutations in KCNJ6 are responsible for the weaver mutation in mice.

 

KCNJ8 mutations cause an elevated ST segment of the EKG, AV blocks, tachycardia, and may cause myocardial infarction.

 

KCNJ10 is expressed in the brain and kidney.

 

KCNJ11 is ATP sensitive and is influenced by metabolic conditions such as hypoxia.  In the substantia nigra, these channels can contribute to seizures.  Mutations can result in hyperinsulinemia hypoglycemia.

 

KCNJ12 is expressed in the heart.

 

KCNJ13 is expressed in the small intestine, stomach, kidney, and CNS (frog small intestine pictured below).

GI TRACT

KCNJ14 is expressed in the motor neurons of the brain.

 

KCNJ15 is expressed in the adult kidney and brain and in the developing kidney and lung.

 

KCNJ16 is expressed in the kidney, pancreas, and thyroid.

 

INWARD RECTIFYING POTASSIUM CHANNELS

K SUBFAMILY channels are open at all membrane potentials and contribute to the resting membrane potential.   All share a common P domain which is important in their selectivity for potassium.  They have 4 transmembrane sections and 2 pores per subunit.

 

KCNK1 is most highly expressed in the brain and heart and is homologous to two genes in C. elegans.

 

KCNK2 is expressed in the brain and lung.

 

KCNK3 is most highly expressed in the pancreas and placenta.

 

KCNK4 is most highly expressed in the pancreas and placenta.

 

KCNK5

 

KCNK6 is expressed in many tissues.

 

KCNK7 is produced in alternate transcripts.

 

KCNK10 is regulated by a variety of neurotransmitter receptors.

 

KCNK12 is most highly expressed in the heart, skeletal muscle, and pancreas.

 

KCNK13 is expressed in olfactory regions, the septum, and in hypothalamic and thalamic nuclei.

 

KCNK15 is most highly expressed in the adrenal gland and pancreas.  Cells of the adrenal gland are depicted below.

ADRENAL GLAND

KCNK16 is located in a cluster which also contains KCNK17 and KCNK5.]

 

KCNK17 is most highly expressed in the liver, lung, placenta, pancreas, small intestine and aorta.

 

Q SUBFAMILY

KCNQ1 mutations can cause Long QT syndrome, decreased heart rate in infants, arrhythmia, and sudden death.

 

KCNQ2 mutations can cause neonatal epilepsy.

 

KCNQ3 mutations can cause neonatal epilepsy.

 

KCNQ4 is expressed in the hair cells of the ear, in the inferior colliculus, and in cochlear nuclei.  It is the first channel known to be expressed in one sensory pathway only.  Mutations can cause deafness.

 

KCNQ5 is expressed in the brain and in muscle and can be spliced to produce different forms.

 

N SUBFAMILY; Calcium Activated

KCNN1

 

KCNN2

 

KCNN3 alleles have been linked to schizophrenia and bipolar disorder.

 

KCNN4 is expressed in the placenta, lung, pancreas, and on T lymphocytes.

 

M SUBFAMILY; Calcium Activated

KCNMA1 is the pore-forming subunit of this channel and is homologous to the Drosophila gene slowpoke.  It is expressed in muscle, neurons (such as those of the cerebellum pictured below), and hair cells and helps to determine the muscle tone of the arterial walls.

CEREBELLUM

The Beta subunits of this channel help to regulate the activity of this channel and can interact with estrogen.

KCNMB1 is primarily expressed in smooth muscle and helps to regulate blood pressure.

 

KCNMB2 is expressed in endocrine cells, smooth muscle, the heart and brain.

 

KCNMB3 is expressed to some degree in most tissues.  One of its alternately spliced forms is expressed only in the beta cells of the pancreas.

 

KCNMB4 is expressed in neural tissue only.

NEURON

SODIUM CHANNELS

Some ion channels, such as some found in the cerebral neurons above, are voltage regulated: at one transmembrane voltage (e.g. when the cell is at rest) the channel is closed and at another voltage (e.g. the cell has been stimulated), the channel is open.  These voltage regulated cells allow action potentials—waves of depolarization which spread over neurons and muscle cells upon stimulation.

CHANNEL

     Virtuallly all protists use calcium to depolarize the cells (with the exception of the heliozoan Actinocoryne contractilis which uses sodium).  Sodium dependent action potentials are typical of animals since the simplest animals which possessed a nervous system, the cnidarians.  The evolution of neurons required a switch to sodium as the depolarizing ion in action potentials; the use of calcium would have resulted in toxic intracellular levels of calcium in rapidly firing neurons (Anderson, 2001).  Sodium transport is linked to the transport of other substances as well.  Microbes can possess symport channels for sodium and glutamate, bile acids, and phosphate and antiport channels (a number of different families) for the export of hydrogen ions (Paulsen, 2000). Voltage-regulated sodium channels are known from bacteria which are similar to voltage regulated calcium channels (Ren, 2001).

     While eukaryotic sodium channels are large proteins, composed of four homologous domains of a potassium-channel like region, a simpler sodium channel is known in bacteria.  It has a single domain, similar to the smaller potassium channels (Catterall, 2001).  All other sodium channels are similar to calcium channels, structurally and functionally.  Sequence analysis suggests that the first voltage regulated sodium channels were derived from ancestral calcium channels before the evolution of the eukaryotes.  Prior to this, potassium channels and ligand-gated channels developed from the ancestral channel.  Two channels, TPC1 from plants and RB21 from fungi and animals, seem to have split from the ancestral Ca/Na channels before duplications led to separate specific channels (Anderson, 2001).

 

1) Voltage Regulated

In vertebrates, voltage regulated sodium channels are composed of 1 large alpha subunit (which contains the channel’s pore) and two beta subunits.  These channels are not only expressed in excitable cells (neurons, muscle) but some nonexcitable cells as well (such as astrocytes and Schwann cells).  All of the alpha subunits form a gene subfamily.  Each alpha subunit has 4 domains and 3 intracellular loops (OMIM).   

          Homologs of the sodium α subunit (which is primarily responsible for the depolarization during an action potential) exist in a diversity of invertebrates, including cnidarians, whose sodium channels are similar to those in mammals (Anderson, 2001; Plummer, 1999).  While invertebrates only have one or two genes for voltage-dependent sodium channels in their genomes, humans and mice possess 11 genes for α subunits of sodium channels, seven of which are largely specific to nervous tissue and 2 additional channels specific to skeletal and cardiac muscle.  As with other gene families (such as the globins and the Hox genes), it appears that genome duplications at the base of the vertebrate lineage and more recent tandem duplications of individual genes are responsible for this expansion.  In the human genome, the genes for voltage-dependent sodium channels are located on four chromosomes with clusters of five tandem genes on chromosome 2 and three tandem genes on chromosome 3 (Lopreato, 2001; Plummer, 1999).

 

SCN1A mutations cause generalized epilepsy, myoclonic epilepsy, and febrile seizures.

 

SCN2A1 mutations can cause febrile seizures.

 

SCN2A2 is expressed moreso than SCN1A I the caudal portions of the CNS.

 

SCN3A is located on chromosome 2q22-4 along with SCN2 genes.

 

SCN4A is expressed in skeletal muscle (pictured below).  Mutations cause paramyotonia and hyperkalemic periodic paralysis.

SKELETAL

SCN5A is expressed in cardiac muscle.  Mutations cause long QT syndrome, heart block, and ventricular arrhythmia.

 

SCN7A is expressed in the lung, heart, dorsal root ganglia, Scwhann cells, and ependymal cells.  It may serve as a sensor for the concentration of sodium in body fluids.

 

SCN8A mutations cause cerebellar abnormalities and affect movement (cerebellum pictured below).

CEREBELLUM

SCN9A is similar to those alpha subunits found in the brain and in muscle and it may represent an evolutionary link between them.

 

SCN11A is expressed in the dorsal root ganglia, trigeminal ganglia, throughout the brain, and even in the spleen and placenta.

DORSAL ROOT GANGLION

The alpha subunits can function alone.  The beta subunits function in membrane localization and the modification of the properties of the alpha subunits.

SCN1B mutations are involved in generalized epilepsy with febrile seizures.

 

SCN2B

 

2)       Non-voltage Regulated

     Non-voltage regulated sodium channels have 3 subunits: alpha, beta, and gamma.  Each of these are homologous and have 2 transmembrane domains.  They are expressed in the epithelia of the lung, the distal convoluted tubules of the kidney, the colon, and some exocrine tissues.  Mutations in any of them can affect blood pressure.

 

SCNN1A can undergo alternate splicing in different tissues of the body; some alleles increase the risk of hypertension.  Mutations can cause pseudohypoaldosteronism type I.

 

SCNN1B mutations in animals produce effects similar to salt-sensitive hypertension in humans.  In humans, mutations can cause Liddle syndrome (with its hyperkalemia, alkalosis, and increased blood pressure).

 

SCNN1γ mutations cause Liddle syndrome and pseudohypoaldosteronism.

Five γ subunits are known in the human genome.  γ1 is expressed in skeletal muscle.  γ2 receptors regulate AMPA receptors (Chu, 2001). 

 

 

SCNN1D is expressed in the gonads, pancreas, and brain.

ACCN (cation channel, amiloride sensitive, neuronal) is homologous to SCNN1A.  While SCNN1A, 1B, and 1G are subunits of the same channel and thus are interdependent, ACCN1 is not affected by the expression of these other genes.  In mice ACCN1 is needed for the sensation of light touch.  Humans also have an ACCN2 gene.  These amiloride sensitive channels were first identified in the worm C. elegans.

 

ASIC4 (acid sensing ion channel 4) is expressed in the pituitary and the inner ear.

 

CALCIUM CHANNELS

     Some types of calcium channel are present in all eukaryotic cells while others are limited to certain cell types.  Some channels are highly specific for calcium entry, while others are nonspecific cation channels (Harteneck, 2000).   The regulation of intracellular calcium levels is an ancient second messenger system.  Calcium pumps originally existed on the cell membrane but were added to the ER in the evolution of eukaryotes.  The ER pumps are homologous to those of the plasma membrane (Sorrentino, 2000).   Calcium functions in intracellular physiological mechanisms and also produces biomineralized protective structures in plants, invertebrates, and vertebrates.  Voltage regulated calcium channels are known in cnidarians (Zoccola, 1999). 

     Calcium channels possess an α subunit which forms the core an additional β, α2δ, and γ subunits. Each subunit is produced by the products of multiple genes.  The subunits which attach to the core help to regulate the channel, for example, in its reaction to changing voltage (Chu, 2001). 

 

The multiple γ subunit genes resulted from the gene duplications early in the evolution of vertebrates (Chu, 2001). 

 

There are two subfamilies of Intracellular calcium release channels (ICRCs): the inositol triphosphate receptor and the ryanodine receptor genes.  The two subfamilies of ICRCs diverged before the evolution of nematodes (there is some evidence of their presence in plants); both nemaotodes and flies possess one  inositol triphosphate receptor and the ryanodine receptor (Sorrentino, 2000). 

 

RyR receptors are expressed in muscle in both invertebrates and vertebrates.  Mammals Ryr1-3 (Sorrentino, 2000). 

 

Ryr1 mutations are involved in malignant hyperthermia and central core disease (Sorrentino, 2000). 

 

TRP CHANNELS

C.elegans possesses 13 TRP channels.  TRP are homolgous to voltage regulated sodium, potassium, and calcium channels.  TRP channels form a number of subfamilies, which can vary in the length of the N terminal region and the number of ankyrin domains located there.  Members of the STRP, OTRP, and LTRP channels are known in both C.elegans and mammals (Harteneck, 2000). 

LTRPC1 (melastin) is expressed in melanocytes and its concentration decreases in cancer (Harteneck, 2000). 

 

 

IONS AND ELECTRICITY

Much of the human body (such as muscle and neurons in the pictures above) runs on electricity.  The impulses transferred over a neuron or a muscle cell are electrical and many cells rely on changing the transmembrane voltage as a part of their function (beginning with the ova which depolarizes upon fertilization, stimulating mechanisms which will prevent the entry of multiple sperm).  A voltage exists across the cell membrane—there are more positive charges outside the cell than inside.  This is the result of the sodium-potassium ion exchange pump which uses ATP to pump potassium into the cell and sodium out of the cell.  Since 3 positive sodium ions are pumped out of the cell every time that 2 positive potassium ions are pumped into the cell, the inside of the cell become negatively charged since there are more positive charges outside than inside.
PUMP


The sodium/potassium ion exchange pumps control osmoregulation, the transport of many organic and inorganic substances, and the resting membrane potential of cells.  The alpha units of the ion pumps are the largest and they perform the ion exchange.  The activity level of the Na+/K+ ATPase has a genetic component, as evidenced from twin studies and studies across ethnic groups.  One recessive allele, when homozygous, increases the number of pumps to about 566/red blood cell from the normal 312 per red blood cell.

In placental mammals, the β-subunits of Na,K-ATPase were modified, moved to the nuclear membrane, and assigned a new function, that of gene regulation of genes involved in TGF-β signaling (Pestov, 2007).

ATP1A1 alleles may be a factor in hypertension.

 

 ATP1A2 mutations result in improper ion concentrations and increase susceptibility to migraine.

 

ATP1A3 is primarily expressed in neural tissue (cerebral tissue pictured below).

CEREBRUM

ATP1A4

 

ATPAL1 has an unknown function.

 

Calcium Pumps

Many members of the gene family which includes the sodium/potassium ion exchange pump function in the transport of calcium.  ATP2A1 is expressed in fast twitch skeletal muscle and is 84% homologous to the pump in slow twitch skeletal muscle.  This calcium pump is located in the sarcoplasmic reticulum.  Mutations result in Brody myopathy which involve muscular problems in exercise.

 

ATP2A2 is experssed in slow twitch muscle, keratinocytes, and fibroblasts. This calcium pump is located in the sarcoplasmic reticulum.   Mutations cause Darrier disease which involves a skin disorder associated with warty plaqus, abnormal nails, and blistering; mild retardation and epilepsy are present in some.

 

ATP3A is a calcium pump of the sarcoplasmic reticulum.

 

K+/H+ Exchange

ATP4A functions in the acid secretion of the stomach.

 

ATP4B is expressed in the DCT of the kidney (the intercaleated cells) and mutations cause renal tubular acidosis.

 

ATP7A is a copper ion pump which is expressed in many tissues.  Mutations cause Menke’s disease and occipital horn syndrome which may involve abnormalities in blood copper levels, very lose skin, hyperflexibility, and aneurisms.

 

ATP7B is a copper transport pump whose mutations cause Wilson disease.

 

ATP2B1 is a plasma membrane calcium pump.

 

ATP2B2 is expressed in stereocilia cells of the ear and Purkinje cells of the cerebellum.  Mutations in mice cause deafness and the mutant deafwaddler phenotype.

ATP2B3 is a calcium pump expressed in the skin and brain.

 

ATP2B4 is a plasma membrane calcium pump.

 

ATP8A pumps amphipathic molecules such as amino phospholipids.  It is expressed in the brain, placenta, heart, and testis.

 

ATP8B pumps amphipathic molecules such as amino phospholipids.  Is most highly expressed in epithelia.  Mutations cause cholestasis with its associated jaundice and affects bile acid transport (liver cells are pictured below).

liver

ATP8B3 is expressed throughout the brain.

 

ATP8B3

 

ATP10C may transport aminophopholipids.  Its expression affects body fat and this gene may be responsible for the lipid abnormalities of the Prader-Willi and Angelman syndromes.

 

ATP11A is a calcium pump.

 

ATP11B is expressed in chromaffin cells, the kidney, ovary, testis, and corpus callosum

The function of the beta subunits of calcium channels in general is not well understood. 

ATPB1 is conserved; the human protein is similar to that found in cartilaginous fish.

 

ATPB2 is expressed in glia and helps neuron migration.  It is also known as AMOG, the adhesion molecule on glia.

 

ATPB3

 

ATPBL1is present in humans but not in mice.

 

ATP2C1 is a calcium pump whose mutations cause Hailey-Hailey disease .