Aquaporins
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Aquaporins, also called water channels, are channel proteins from a larger
family Family (from ) is a Social group, group of people related either by consanguinity (by recognized birth) or Affinity (law), affinity (by marriage or other relationship). It forms the basis for social order. Ideally, families offer predictabili ...
of
major intrinsic proteins Major intrinsic proteins comprise a large superfamily of transmembrane protein channels that are grouped together on the basis of homology. The MIP superfamily includes three subfamilies: aquaporins, aquaglyceroporins and S-aquaporins. # The aqua ...
that form pores in the
membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
of biological cells, mainly facilitating transport of
water Water is an inorganic compound with the chemical formula . It is a transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance. It is the main constituent of Earth's hydrosphere and the fluids of all known liv ...
between cells. The cell membranes of a variety of different
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
,
fungi A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...
,
animal Animals are multicellular, eukaryotic organisms in the Biology, biological Kingdom (biology), kingdom Animalia (). With few exceptions, animals heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, ...
and
plant cell Plant cells are the cells present in Viridiplantae, green plants, photosynthetic eukaryotes of the kingdom Plantae. Their distinctive features include primary cell walls containing cellulose, hemicelluloses and pectin, the presence of plastids ...
s contain aquaporins through which water can flow more rapidly into and out of the cell than by diffusing through the
phospholipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes form a continuous barrier around all cells. The cell membranes of almost all organisms and many viruses are made of a l ...
. Aquaporins have six membrane-spanning alpha helical domains with both carboxylic and amino terminals on the cytoplasmic side. Two hydrophobic loops contain conserved
asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...
alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group sid ...
("NPA motif") which form a barrel surrounding a central pore-like region that contains additional protein density. Because aquaporins are usually always open and are prevalent in just about every cell type, this leads to a misconception that water readily passes through the cell membrane down its concentration gradient. Water can pass through the cell membrane through simple diffusion because it is a small molecule, and through
osmosis Osmosis (, ) is the spontaneous net movement or diffusion of solvent molecules through a selectively permeable membrane, selectively-permeable membrane from a region of high water potential (region of lower solute concentration) to a region of ...
, in cases where the concentration of water outside of the cell is greater than that of the inside. However, because water is a
polar molecule In chemistry, polarity is a separation of electric charge leading to a molecule or its chemical groups having an electric dipole moment, with a negatively charged end and a positively charged end. Polar molecules must contain one or more polar ...
this process of simple diffusion is relatively slow, and in tissues with high water permeability the majority of water passes through aquaporin. The 2003
Nobel Prize in Chemistry The Nobel Prize in Chemistry () is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outst ...
was awarded jointly to
Peter Agre Peter Agre (; born January 30, 1949) is Nobel Laureate American physician, molecular biologist, Bloomberg Distinguished Professorships, Bloomberg Distinguished Professor at the Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Sch ...
for the discovery of aquaporins and Roderick MacKinnon for his work on the structure and mechanism of
potassium channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of ...
s. Genetic defects involving aquaporin
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s have been associated with several human diseases including nephrogenic
diabetes insipidus Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. ...
and
neuromyelitis optica Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord ( myelitis).Banerjee S, Butcher R. Rituximab for the Treatment o ...
.


History

The mechanism of facilitated water transport and the probable existence of water pores has attracted researchers since 1957. In most cells, water moves in and out by
osmosis Osmosis (, ) is the spontaneous net movement or diffusion of solvent molecules through a selectively permeable membrane, selectively-permeable membrane from a region of high water potential (region of lower solute concentration) to a region of ...
through the lipid component of cell membranes. Due to the relatively high water permeability of some
epithelial cells Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
, it was long suspected that some additional mechanism for water transport across membranes must exist. Solomon and his co-workers performed pioneering work on water permeability across the cell membrane in the late 1950s. In the mid-1960s an alternative hypothesis (the "partition–diffusion model") sought to establish that the water molecules partitioned between the water phase and the lipid phase and then diffused through the membrane, crossing it until the next interphase where they left the lipid and returned to an aqueous phase. Studies by Parisi, Edelman, Carvounis et al. accented not only the importance of the presence of water channels but also the possibility to regulate their permeability properties. In 1990, Verkman's experiments demonstrated functional expression of water channels, indicating that water channels are effectively proteins.


Discovery

It was not until 1992 that the first aquaporin, 'aquaporin-1' (originally known as CHIP 28), was reported by
Peter Agre Peter Agre (; born January 30, 1949) is Nobel Laureate American physician, molecular biologist, Bloomberg Distinguished Professorships, Bloomberg Distinguished Professor at the Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Sch ...
, of
Johns Hopkins University The Johns Hopkins University (often abbreviated as Johns Hopkins, Hopkins, or JHU) is a private university, private research university in Baltimore, Maryland, United States. Founded in 1876 based on the European research institution model, J ...
. In 1999, together with other research teams, Agre reported the first high-resolution images of the three-dimensional structure of an aquaporin, namely, aquaporin-1. Further studies using
supercomputer A supercomputer is a type of computer with a high level of performance as compared to a general-purpose computer. The performance of a supercomputer is commonly measured in floating-point operations per second (FLOPS) instead of million instruc ...
simulations identified the pathway of water as it moved through the channel and demonstrated how a pore can allow water to pass without the passage of small solutes. The pioneering research and subsequent discovery of water channels by Agre and his colleagues won Agre the
Nobel Prize The Nobel Prizes ( ; ; ) are awards administered by the Nobel Foundation and granted in accordance with the principle of "for the greatest benefit to humankind". The prizes were first awarded in 1901, marking the fifth anniversary of Alfred N ...
in Chemistry in 2003. Agre said he discovered aquaporins "by serendipity." He had been studying the Rh blood group
antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s and had isolated the Rh molecule, but a second molecule, 28 kilodaltons in size (and therefore called 28K) kept appearing. At first they thought it was a Rh molecule fragment, or a contaminant, but it turned out to be a new kind of molecule with unknown function. It was present in structures such as kidney tubules and red blood cells, and related to proteins of diverse origins, such as in fruit fly brain, bacteria, the lens of the eye, and plant tissue. To prove that 28KDa is functioning as a water channel, Agre collaborated with two colleagues at Johns Hopkins University. They used frog eggs—Xenopus laevis oocytes. Frog oocytes are known to have a plasma membrane with very low water permeability; normally they burst when placed in a hypotonic solution. They injected messenger RNA encoding the 28K protDaein into the oocytes. The oocytes expressing 28K rapiDadly swelled from the influx of water and burst. In contrast, control oocytes remaiwithout the 28K ned intact. This compelling result provided definitive functional evidence that 28 kDa. However the first report of protein-mediated water transport through membranes was by Gheorghe Benga and others in 1986, prior to Agre's first publication on the topic. This led to a controversy that Benga's work had not been adequately recognized either by Agre or by the Nobel Prize Committee.


Function

Aquaporins are "the plumbing system for cells". Water moves through cells in an organized way, most rapidly in tissues that have aquaporin water channels. For many years, scientists assumed that water leaked through the cell membrane, and some water does. However, this did not explain how water could move so quickly through some cells.A Conversation With Peter Agre: Using a Leadership Role to Put a Human Face on Science
By Claudia Dreifus, New York Times, January 26, 2009
Aquaporins selectively conduct
water Water is an inorganic compound with the chemical formula . It is a transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance. It is the main constituent of Earth's hydrosphere and the fluids of all known liv ...
molecule A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...
s in and out of the cell, while preventing the passage of
ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
s and other
solutes In chemistry, a solution is defined by IUPAC as "A liquid or solid phase containing more than one substance, when for convenience one (or more) substance, which is called the solvent, is treated differently from the other substances, which are ...
. Also known as water channels, aquaporins are integral membrane pore proteins. Some of them, known as aquaglyceroporins, also transport other small uncharged dissolved molecules including ammonia, CO2,
glycerol Glycerol () is a simple triol compound. It is a colorless, odorless, sweet-tasting, viscous liquid. The glycerol backbone is found in lipids known as glycerides. It is also widely used as a sweetener in the food industry and as a humectant in pha ...
, and urea. For example, the aquaporin 3 channel has a pore width of 8–10 Ångströms and allows the passage of hydrophilic molecules ranging between 150 and 200 Da. However, the water pores completely block ions including
protons A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' ( elementary charge). Its mass is slightly less than the mass of a neutron and approximately times the mass of an electron (the pro ...
, essential to conserve the membrane's electrochemical potential difference. Water molecules traverse through the pore of the channel in single file. The presence of water channels increases membrane permeability to water. These are also essential for the water transport system in plants and tolerance to drought and salt stresses.


Structure

Aquaporin proteins are composed of a bundle of six
transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
α-helices. They are embedded in the cell membrane. The amino and carboxyl ends face the inside of the cell. The amino and carboxyl halves resemble each other, apparently repeating a pattern of nucleotides. This may have been created by the doubling of a formerly half-sized gene. Between the helices are five regions (A – E) that loop into or out of the cell membrane, two of them hydrophobic (B, E), with an asparagine–proline–alanine ("NPA motif") pattern. They create a distinctive hourglass shape, making the water channel narrow in the middle and wider at each end. Another and even narrower place in the AQP1 channel is the "ar/R selectivity filter", a cluster of amino acids enabling the aquaporin to selectively let through or block the passage of different molecules. Aquaporins form four-part clusters (tetramers) in the cell membrane, with each of the four
monomer A monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called polymerization. Classification Chemis ...
s acting as a water channel. Different aquaporins have different sized water channels, the smallest types allowing nothing but water through. X-ray profiles show that aquaporins have two conical entrances. This hourglass shape could be the result of a natural selection process toward optimal permeability. It has been shown that conical entrances with suitable opening angle can indeed provide a large increase of the hydrodynamic channel permeability.


NPA motif

Aquaporin channels appear in simulations to allow only water to pass, as the molecules effectively queue up in single file. Guided by the aquaporin's local electric field, the oxygen in each water molecule faces forwards as it enters, turning around half way along and leaving with the oxygen facing backwards. The arrangement of opposite-facing electrostatic potentials in the two halves of the channel prevents the flow of protons but permits water to pass freely.


ar/R selectivity filter

The aromatic/
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
or "ar/R" selectivity filter is a cluster of
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s that help bind to water molecules and exclude other molecules that may try to enter the pore. It is the mechanism by which the aquaporin is able to selectively bind water molecules and so to allow them through, and to prevent other molecules from entering. The ar/R filter is made of two amino acid groups from helices B (HB) and E (HE) and two groups from loop E (LE1, LE2), from the two sides of the NPA motif. Its usual position is 8 Å on the outer side of the NPA motif; it is typically the tightest part of the channel. Its narrowness weakens the hydrogen bonds between water molecules, enabling the arginines, which carry a positive charge, to interact with the water molecules and to filter out undesirable protons.


Taxonomic distribution


In mammals

There are thirteen known types of aquaporins in mammals; six of these are located in the kidney, but the existence of many more is suspected. The most studied aquaporins are compared in the following table:


In plants

In plants, water is taken up from the soil through the roots, where it passes from the cortex into the vascular tissues. There are three routes for water to flow in these tissues, known as the apoplastic, symplastic and transcellular pathways. Specifically, aquaporins are found in the vacuolar membrane, in addition to the plasma membrane of plants; the transcellular pathway involves transport of water across the plasma and vacuolar membranes. When plant roots are exposed to
mercuric chloride Mercury(II) chloride (mercury bichloride, mercury dichloride, mercuric chloride), historically also sulema or corrosive sublimate, is the inorganic chemical compound of mercury and chlorine with the formula HgCl2, used as a laboratory reagent. ...
, which is known to inhibit aquaporins, the flow of water is greatly reduced while the flow of ions is not, supporting the view that there exists a mechanism for water transport independent of the transport of ions: aquaporins. Aquaporins can play a major role in extension growth by allowing an influx of water into expanding cells - a process necessary to sustain plant development. Plant aquaporins are important for mineral nutrition and ion detoxification; these are both essential for the homeostasis of minerals such as boron. Aquaporins in plants are separated into four main homologous subfamilies, or groups: * Plasma membrane Intrinsic Protein (PIP) * Tonoplast Intrinsic Protein (TIP) * Nodulin-26 like Intrinsic Protein (NIP) * Small basic Intrinsic Protein (SIP) These five subfamilies have later been divided into smaller evolutionary subgroups based on their DNA sequence. PIPs cluster into two subgroups, PIP1 and PIP2, whilst TIPs cluster into 5 subgroups, TIP1, TIP2, TIP3, TIP4 and TIP5. Each subgroup is again split up into
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
s e.g. PIP1;1, PIP1;2. As isoforms nomenclature are historically based on functional parameters rather than evolutive ones, several novel propositions on plant aquaporines have been arisen with the study of the evolutionary relationships between the different aquaporins. Within the various selection of aquaporin isoforms in plants, there are also unique patterns of cell- and tissue-specific expression. When plant aquaporins are silenced, the hydraulic conductance and
photosynthesis Photosynthesis ( ) is a system of biological processes by which photosynthetic organisms, such as most plants, algae, and cyanobacteria, convert light energy, typically from sunlight, into the chemical energy necessary to fuel their metabo ...
of the leaf decrease. When gating of plant aquaporins occurs, it stops the flow of water through the pore of the protein. This may happen for various reasons, for example when the plant contains low amounts of cellular water due to drought. The gating of an aquaporin is carried out by an interaction between a gating mechanism and the aquaporin, which causes a 3D change in the protein so that it blocks the pore and, thus, disallows the flow of water through the pore. In plants, there are at least two forms of aquaporin gating: gating by the dephosphorylation of certain serine residues, in response to drought, and the
protonation In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), usually denoted by H+, to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brø ...
of specific
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
residues, in response to flooding. The phosphorylation of an aquaporin is involved in the opening and closing of petals in response to temperature.


In Heteroconts

Specific aquaporins called Large Intrinsic Proteins (LIP) have been found in Heterokonts, including
diatoms A diatom (Neo-Latin ''diatoma'') is any member of a large group comprising several Genus, genera of algae, specifically microalgae, found in the oceans, waterways and soils of the world. Living diatoms make up a significant portion of Earth's B ...
and
brown algae Brown algae (: alga) are a large group of multicellular algae comprising the class (biology), class Phaeophyceae. They include many seaweeds located in colder waters of the Northern Hemisphere. Brown algae are the major seaweeds of the temperate ...
. LIPs contain an NPM-motif in place of the second conserved NPA-motif typical of the majority of MIPs.


In other organisms

Aquaporins have been discovered in the fungi ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
'' (yeast), ''
Dictyostelium ''Dictyostelium'' is a genus of single- and multi-celled eukaryotic, phagotrophic bacterivores. Though they are Protista and in no way fungal, they traditionally are known as "slime molds". They are present in most terrestrial ecosystems a ...
'', '' Candida'' and '' Ustilago'' and the protozoans ''
Trypanosoma ''Trypanosoma'' is a genus of kinetoplastids (class Trypanosomatidae), a monophyletic group of unicellular parasitic flagellate protozoa. Trypanosoma is part of the phylum Euglenozoa. The name is derived from the Ancient Greek ''trypano-'' (b ...
'' and ''
Plasmodium ''Plasmodium'' is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of ''Plasmodium'' species involve development in a Hematophagy, blood-feeding insect host (biology), host which then inj ...
''.


Clinical significance

There have been two clear examples of diseases identified as resulting from mutations in aquaporins: mutations in the aquaporin-2
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
cause hereditary nephrogenic
diabetes insipidus Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. ...
in humans, while mice
homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
for inactivating mutations in the aquaporin-0 gene develop
congenital A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision of the eye. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colours, blurry or double vision, halos around ligh ...
. A small number of people have been identified with severe or total deficiency in aquaporin-1. They are, in general, healthy, but exhibit a defect in the ability to concentrate solutes in the urine and to conserve water when deprived of drinking water. Mice with targeted deletions in aquaporin-1 also exhibit a deficiency in water conservation due to an inability to concentrate solutes in the kidney medulla by
countercurrent multiplication Countercurrent may refer to: *Countercurrent pool *Countercurrent exchange *Countercurrent chromatography *Equatorial Counter Current *''Counter-Currents'', an alt-right online publication *''Countercurrents.org'', an Indian news website *two polit ...
. Aquaporins play a key role in acquired forms of nephrogenic diabetes insipidus, disorders that cause increased urine production. Aquaporin 2 is regulated by vasopressin which, when bound to the cell-surface receptor, activates the cAMP signaling pathway. This results in aquaporin-2 containing vesicles to increase water uptake and return to circulation. Mutation of the aquaporin 2 vasopressin receptor is a cause of acquired diabetes insipidus. In rats, acquired nephrogenic diabetes insipidus can be caused by impaired regulation of aquaporin-2 due to administration of
lithium Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...
salts, low potassium concentrations in the blood (
hypokalemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an a ...
) and high
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
concentrations in the blood (
hypercalcemia Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range for total calcium is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L def ...
).
Autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
reactions against aquaporin 4 in humans produce
Devic's disease Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis).Banerjee S, Butcher R. Rituximab for the Treatment of ...
. If aquaporin could be manipulated, that could potentially solve medical problems such as fluid retention in heart disease and brain edema after stroke.


References


External links

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Animation
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file at nobel.se) * * {{Ion channels, g4 Integral membrane proteins Biology of bipolar disorder