The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. The brain is located in the head close to the sensory organs for senses such as vision; the brain is the most complex organ in a vertebrate's body. In a human, the cerebral cortex contains 14–16 billion neurons, the estimated number of neurons in the cerebellum is 55–70 billion; each neuron is connected by synapses to several thousand other neurons. These neurons communicate with one another by means of long protoplasmic fibers called axons, which carry trains of signal pulses called action potentials to distant parts of the brain or body targeting specific recipient cells. Physiologically, the function of the brain is to exert centralized control over the other organs of the body; the brain acts on the rest of the body both by generating patterns of muscle activity and by driving the secretion of chemicals called hormones. This centralized control allows coordinated responses to changes in the environment.
Some basic types of responsiveness such as reflexes can be mediated by the spinal cord or peripheral ganglia, but sophisticated purposeful control of behavior based on complex sensory input requires the information integrating capabilities of a centralized brain. The operations of individual brain cells are now understood in considerable detail but the way they cooperate in ensembles of millions is yet to be solved. Recent models in modern neuroscience treat the brain as a biological computer different in mechanism from an electronic computer, but similar in the sense that it acquires information from the surrounding world, stores it, processes it in a variety of ways; this article compares the properties of brains across the entire range of animal species, with the greatest attention to vertebrates. It deals with the human brain insofar; the ways in which the human brain differs from other brains are covered in the human brain article. Several topics that might be covered here are instead covered there because much more can be said about them in a human context.
The most important is brain disease and the effects of brain damage, that are covered in the human brain article. The shape and size of the brain varies between species, identifying common features is difficult. There are a number of principles of brain architecture that apply across a wide range of species; some aspects of brain structure are common to the entire range of animal species. The simplest way to gain information about brain anatomy is by visual inspection, but many more sophisticated techniques have been developed. Brain tissue in its natural state is too soft to work with, but it can be hardened by immersion in alcohol or other fixatives, sliced apart for examination of the interior. Visually, the interior of the brain consists of areas of so-called grey matter, with a dark color, separated by areas of white matter, with a lighter color. Further information can be gained by staining slices of brain tissue with a variety of chemicals that bring out areas where specific types of molecules are present in high concentrations.
It is possible to examine the microstructure of brain tissue using a microscope, to trace the pattern of connections from one brain area to another. The brains of all species are composed of two broad classes of cells: neurons and glial cells. Glial cells come in several types, perform a number of critical functions, including structural support, metabolic support and guidance of development. Neurons, are considered the most important cells in the brain; the property that makes neurons unique is their ability to send signals to specific target cells over long distances. They send these signals by means of an axon, a thin protoplasmic fiber that extends from the cell body and projects with numerous branches, to other areas, sometimes nearby, sometimes in distant parts of the brain or body; the length of an axon can be extraordinary: for example, if a pyramidal cell of the cerebral cortex were magnified so that its cell body became the size of a human body, its axon magnified, would become a cable a few centimeters in diameter, extending more than a kilometer.
These axons transmit signals in the form of electrochemical pulses called action potentials, which last less than a thousandth of a second and travel along the axon at speeds of 1–100 meters per second. Some neurons emit action potentials at rates of 10–100 per second in irregular patterns. Axons transmit signals to other neurons by means of specialized junctions called synapses. A single axon may make as many as several thousand synaptic connections with other cells; when an action potential, traveling along an axon, arrives at a synapse, it causes a chemical called a neurotransmitter to be released. The neurotransmitter binds to receptor molecules in the membrane of the target cell. Synapses are the key functional elements of the brain; the essential function of the brain is cell-to-cell communication, synapses are the points at which communication occurs. The human brain has been estimated to contain 100 trillion synapses; the functions of these synapses are diverse: some are excitatory.
Sense of balance
The sense of balance or equilibrioception is one of the physiological senses related to balance. It helps prevent animals from falling over when standing or moving. Balance is the result of a number of body systems working together: the eyes and the body's sense of where it is in space ideally need to be intact; the vestibular system, the region of the inner ear where three semicircular canals converge, works with the visual system to keep objects in focus when the head is moving. This is called the vestibulo-ocular reflex; the balance system works with the skeletal systems to maintain orientation or balance. Visual signals sent to the brain about the body's position in relation to its surroundings are processed by the brain and compared to information from the vestibular and skeletal systems. In the vestibular system, equilibrioception is determined by the level of a fluid called endolymph in the labyrinth, a complex set of tubing in the inner ear; when the sense of balance is interrupted it causes dizziness and nausea.
Balance can be upset by Ménière's disease, superior canal dehiscence syndrome, an inner ear infection, by a bad common cold affecting the head or a number of other medical conditions including but not limited to vertigo. It can be temporarily disturbed by quick or prolonged acceleration, for example riding on a merry-go-round. Blows can affect equilibrioreception those to the side of the head or directly to the ear. Most astronauts find that their sense of balance is impaired when in orbit because they are in a constant state of weightlessness; this causes. This overview explains acceleration as its processes are interconnected with balance. There are five sensory organs innervated by the vestibular nerve; each semicircular canal is a thin tube that doubles in thickness at a point called osseous ampullae. At their center-base each contains an ampullary cupula; the cupula is a gelatin bulb connected to stereocilia, affected by the relative movement of the endolymph it is bathed in. Since the cupula is part of the bony labyrinth it rotates along with actual head movement unable to cause stimulation by itself.
Endolymph follows the rotation of the canal, due to inertia its movement lags behind that of the bony labyrinth. The delayed movement of the endolymph bends and activates the cupula, signalling to the body that it has moved in space. After any extended rotation the endolymph catches up to the canal and the cupula returns to its upright position and resets; when extended rotation ceases, endolymph continues, which bends and activates the cupula once again to signal a change in movement. Pilots doing long banked turns begin to feel upright. Stereocilia bend causing chemical reactions in the crita ampullaris; the HSCC handles head rotations about a vertical axis, SSCC handles head movement about a lateral axis, PSCC handles head rotation about a rostral-caudal axis. E.g. HSCC: looking side to side. SCC sends adaptive signals, unlike the otolith organs. A shift in the otolithic membrane that stimulates the cilia is considered the state of the body until the cilia are once again stimulated. E.g. lying down stimulates cilia and standing up stimulates cilia, for the time spent lying the signal that you are lying remains active though the membrane resets.
Otolithic organs have a thick, heavy gelatin membrane that, due to inertia, lags behind and continues ahead past the macula it overlays and activating the contained cilia. Utricle responds to linear accelerations and head-tilts in the horizontal plane, whereas saccule responds to linear accelerations and head-tilts in the vertical plane. Otolithic organs update the brain on the head-location. Kinocilium are positioned in the center of the bundle. If stereocilia go towards kinocilium depolarization occurs causing more neurotransmitter, more vestibular nerve firings as compared to when stereocilia tilt away from kinocilium. First order vestibular nuclei project to IVN, MVN, SVN; the inferior cerebellar peduncle is the largest center. It is the area of integration between proprioceptive, vestibular inputs to aid in unconscious maintenance of balance and posture. Inferior olive nucleus aids in complex motor tasks by encoding coordinating timing sensory info. Cerebellar vermis has three main parts: vestibulocerebellum, spinocerebellum [integrates visual, auditory and balance info to act out body and limb movements.
Trigeminal and dorsal column proprioceptive input, thalamus, reticular formation and vestibular nuclei out
Hearing, or auditory perception, is the ability to perceive sounds by detecting vibrations, changes in the pressure of the surrounding medium through time, through an organ such as the ear. The academic field concerned with hearing is auditory science. Sound may be heard through liquid, or gaseous matter, it is one of the traditional five senses. In humans and other vertebrates, hearing is performed by the auditory system: mechanical waves, known as vibrations are detected by the ear and transduced into nerve impulses that are perceived by the brain. Like touch, audition requires sensitivity to the movement of molecules in the world outside the organism. Both hearing and touch are types of mechanosensation. There are three main components of the human ear: the outer ear, the middle ear, the inner ear; the outer ear includes the pinna, the visible part of the ear, as well as the ear canal which terminates at the eardrum called the tympanic membrane. The pinna serves to focus sound waves through the ear canal toward the eardrum.
Because of the asymmetrical character of the outer ear of most mammals, sound is filtered differently on its way into the ear depending on what vertical location it is coming from. This gives these animals the ability to localize sound vertically; the eardrum is an airtight membrane, when sound waves arrive there, they cause it to vibrate following the waveform of the sound. The middle ear consists of a small air-filled chamber, located medial to the eardrum. Within this chamber are the three smallest bones in the body, known collectively as the ossicles which include the malleus and stapes, they aid in the transmission of the vibrations from the eardrum into the cochlea. The purpose of the middle ear ossicles is to overcome the impedance mismatch between air waves and cochlear waves, by providing impedance matching. Located in the middle ear are the stapedius muscle and tensor tympani muscle, which protect the hearing mechanism through a stiffening reflex; the stapes transmits sound waves to the inner ear through the oval window, a flexible membrane separating the air-filled middle ear from the fluid-filled inner ear.
The round window, another flexible membrane, allows for the smooth displacement of the inner ear fluid caused by the entering sound waves. The inner ear consists of the cochlea, a spiral-shaped, fluid-filled tube, it is divided lengthwise by the organ of Corti, the main organ of mechanical to neural transduction. Inside the organ of Corti is the basilar membrane, a structure that vibrates when waves from the middle ear propagate through the cochlear fluid – endolymph; the basilar membrane is tonotopic, so that each frequency has a characteristic place of resonance along it. Characteristic frequencies are high at the basal entrance to the cochlea, low at the apex. Basilar membrane motion causes depolarization of the hair cells, specialized auditory receptors located within the organ of Corti. While the hair cells do not produce action potentials themselves, they release neurotransmitter at synapses with the fibers of the auditory nerve, which does produce action potentials. In this way, the patterns of oscillations on the basilar membrane are converted to spatiotemporal patterns of firings which transmit information about the sound to the brainstem.
The sound information from the cochlea travels via the auditory nerve to the cochlear nucleus in the brainstem. From there, the signals are projected to the inferior colliculus in the midbrain tectum; the inferior colliculus integrates auditory input with limited input from other parts of the brain and is involved in subconscious reflexes such as the auditory startle response. The inferior colliculus in turn projects to the medial geniculate nucleus, a part of the thalamus where sound information is relayed to the primary auditory cortex in the temporal lobe. Sound is believed to first become consciously experienced at the primary auditory cortex. Around the primary auditory cortex lies Wernickes area, a cortical area involved in interpreting sounds, necessary to understand spoken words. Disturbances at any of these levels can cause hearing problems if the disturbance is bilateral. In some instances it can lead to auditory hallucinations or more complex difficulties in perceiving sound. Hearing can be measured by behavioral tests using an audiometer.
Electrophysiological tests of hearing can provide accurate measurements of hearing thresholds in unconscious subjects. Such tests include auditory brainstem evoked potentials, otoacoustic emissions and electrocochleography. Technical advances in these tests have allowed hearing screening for infants to become widespread; the hearing structures of many species have defense mechanisms against injury. For example, the muscles of the middle ear in many mammals contract reflexively in reaction to loud sounds which may otherwise injure the hearing ability of the organism. There are several different types of hearing loss: Conductive hearing loss, sensorineural hearing loss and mixed types. Conductive hearing loss Sensorineural hearing loss Mixed hearing lossThere are defined degrees of hearing loss: Mild hearing loss - People with mild hearing loss have difficulties keeping up with conversations in noisy surroundings; the most quiet sounds that people with mild hearing loss can hear with their better ear are between 25 and 40 dB HL.
Moderate hearing loss - People with moderate hearing loss have difficulty keeping up with conversations when they are not using a hearing aid. On average, the most quiet sounds heard by
The endoplasmic reticulum is a type of organelle found in eukaryotic cells that forms an interconnected network of flattened, membrane-enclosed sacs or tube-like structures known as cisternae. The membranes of the ER are continuous with the outer nuclear membrane; the endoplasmic reticulum occurs in most types of eukaryotic cells, but is absent from red blood cells and spermatozoa. There are two types of ER: smooth endoplasmic reticulum; the outer face of the rough endoplasmic reticulum is studded with ribosomes that are the sites of protein synthesis. The rough endoplasmic reticulum is prominent in cells such as hepatocytes; the smooth endoplasmic reticulum lacks ribosomes and functions in lipid synthesis but not metabolism, the production of steroid hormones, detoxification. The smooth ER is abundant in mammalian liver and gonad cells; the ER was observed with light microscope by Garnier in 1897, who coined the term "ergastoplasm". With electron microscopy, the lacy membranes of the endoplasmic reticulum were first seen in 1945 by Keith R. Porter, Albert Claude, Ernest F. Fullam.
The word "reticulum", which means "network", was applied by Porter in 1953 to describe this fabric of membranes. The general structure of the endoplasmic reticulum is a network of membranes called cisternae; these sac-like structures are held together by the cytoskeleton. The phospholipid membrane encloses the cisternal space, continuous with the perinuclear space but separate from the cytosol; the functions of the endoplasmic reticulum can be summarized as the synthesis and export of proteins and membrane lipids, but varies between ER and cell type and cell function. The quantity of both rough and smooth endoplasmic reticulum in a cell can interchange from one type to the other, depending on the changing metabolic activities of the cell. Transformation can include embedding of new proteins in membrane as well as structural changes. Changes in protein content may occur without noticeable structural changes; the surface of the rough endoplasmic reticulum is studded with protein-manufacturing ribosomes giving it a "rough" appearance.
The binding site of the ribosome on the rough endoplasmic reticulum is the translocon. However, the ribosomes are not a stable part of this organelle's structure as they are being bound and released from the membrane. A ribosome only binds to the RER; this special complex forms when a free ribosome begins translating the mRNA of a protein destined for the secretory pathway. The first 5–30 amino acids polymerized encode a signal peptide, a molecular message, recognized and bound by a signal recognition particle. Translation pauses and the ribosome complex binds to the RER translocon where translation continues with the nascent protein forming into the RER lumen and/or membrane; the protein is processed in the ER lumen by an enzyme. Ribosomes at this point may be released back into the cytosol; the membrane of the rough endoplasmic reticulum forms large double membrane sheets that are located near, continuous with, the outer layer of the nuclear envelope. The double membrane sheets are stacked and connected through several right or left-handed helical ramps, the so-called Terasaki ramps, giving rise to a structure resembling a multi-storey car park.
Although there is no continuous membrane between the endoplasmic reticulum and the Golgi apparatus, membrane-bound transport vesicles shuttle proteins between these two compartments. Vesicles are surrounded by coating proteins called COPI and COPII. COPII targets vesicles to the Golgi apparatus and COPI marks them to be brought back to the rough endoplasmic reticulum; the rough endoplasmic reticulum works in concert with the Golgi complex to target new proteins to their proper destinations. A second method of transport out of the endoplasmic reticulum involves areas called membrane contact sites, where the membranes of the endoplasmic reticulum and other organelles are held together, allowing the transfer of lipids and other small molecules; the rough endoplasmic reticulum is key in multiple functions: Manufacture of lysosomal enzymes with a mannose-6-phosphate marker added in the cis-Golgi network. Manufacture of secreted proteins, either secreted constitutively with no tag or secreted in a regulatory manner involving clathrin and paired basic amino acids in the signal peptide.
Integral membrane proteins that stay embedded in the membrane as vesicles exit and bind to new membranes. Rab proteins are key in targeting the membrane. Initial glycosylation as assembly continues; this is N-linked. N-linked glycosylation: If the protein is properly folded, Oligosaccharyltransferase recognizes the AA sequence NXS or NXT and adds a 14-sugar backbone to the side-chain nitrogen of Asn. In most cells the smooth endoplasmic reticulum is scarce. Instead there are areas where the ER is smooth and rough, this area is called the transitional ER; the transitional ER gets its name. These are areas where the transport vesicles that contain lipids and proteins made in the ER, detach from the ER and start moving to the Golgi apparatus. Specialized cells can have a lot of smooth endoplasmic reticulum and in these cells the smooth ER has many functions
Chromosome 4 is one of the 23 pairs of chromosomes in humans. People have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs and represents between 6 and 6.5 percent of the total DNA in cells. The chromosome is ~191 megabases in length. In a 2012 paper, seven hundred and fifty seven protein-encoding genes were identified on this chromosome. Two-hundred and eleven of these coding sequences did not have any experimental evidence at the protein level, in 2012. Two-hundred and seventy-one appear to be membrane proteins. Fifty-four have been classified as cancer-associated proteins; the following are some of the gene count estimates of human chromosome 4. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies. Among various projects, the collaborative consensus coding sequence project takes an conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
The following is a partial list of genes on human chromosome 4. For complete list, see the link in the infobox on the right; the following are some of the diseases related to genes located on chromosome 4: National Institutes of Health. "Chromosome 4". Genetics Home Reference. Retrieved 2017-05-06. "Chromosome 4". Human Genome Project Information Archive 1990–2003. Retrieved 2017-05-06
Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis and counselling people with genetic disorders would be considered part of medical genetics. In contrast, the study of non-medical phenotypes such as the genetics of eye color would be considered part of human genetics, but not relevant to medical genetics. Genetic medicine is a newer term for medical genetics and incorporates areas such as gene therapy, personalized medicine, the emerging new medical specialty, predictive medicine. Medical genetics encompasses many different areas, including clinical practice of physicians, genetic counselors, nutritionists, clinical diagnostic laboratory activities, research into the causes and inheritance of genetic disorders.
Examples of conditions that fall within the scope of medical genetics include birth defects and dysmorphology, mental retardation, mitochondrial disorders, skeletal dysplasia, connective tissue disorders, cancer genetics and prenatal diagnosis. Medical genetics is becoming relevant to many common diseases. Overlaps with other medical specialties are beginning to emerge, as recent advances in genetics are revealing etiologies for neurologic, cardiovascular, ophthalmologic, renal and dermatologic conditions; the medical genetics community is involved with individuals who have undertaken elective genetic and genomic testing. In some ways, many of the individual fields within medical genetics are hybrids between clinical care and research; this is due in part to recent advances in science and technology that have enabled an unprecedented understanding of genetic disorders. Clinical genetics is the practice of clinical medicine with particular attention to hereditary disorders. Referrals are made to genetics clinics for a variety of reasons, including birth defects, developmental delay, epilepsy, short stature, many others.
Examples of genetic syndromes that are seen in the genetics clinic include chromosomal rearrangements, Down syndrome, DiGeorge syndrome, Fragile X syndrome, Marfan syndrome, Neurofibromatosis, Turner syndrome, Williams syndrome. In the United States, Doctors who practice clinical genetics are accredited by the American Board of Medical Genetics and Genomics. In order to become a board-certified practitioner of Clinical Genetics, a physician must complete a minimum of 24 months of training in a program accredited by the ABMGG. Individuals seeking acceptance into clinical genetics training programs must hold an M. D. or D. O. degree and have completed a minimum of 24 months of training in an ACGME-accredited residency program in internal medicine, pediatrics and gynecology, or other medical specialty. Metabolic genetics involves the diagnosis and management of inborn errors of metabolism in which patients have enzymatic deficiencies that perturb biochemical pathways involved in metabolism of carbohydrates, amino acids, lipids.
Examples of metabolic disorders include galactosemia, glycogen storage disease, lysosomal storage disorders, metabolic acidosis, peroxisomal disorders and urea cycle disorders. Cytogenetics is the study of chromosomes and chromosome abnormalities. While cytogenetics relied on microscopy to analyze chromosomes, new molecular technologies such as array comparative genomic hybridization are now becoming used. Examples of chromosome abnormalities include aneuploidy, chromosomal rearrangements, genomic deletion/duplication disorders. Molecular genetics involves the discovery of and laboratory testing for DNA mutations that underlie many single gene disorders. Examples of single gene disorders include achondroplasia, cystic fibrosis, Duchenne muscular dystrophy, hereditary breast cancer, Huntington disease, Marfan syndrome, Noonan syndrome, Rett syndrome. Molecular tests are used in the diagnosis of syndromes involving epigenetic abnormalities, such as Angelman syndrome, Beckwith-Wiedemann syndrome, Prader-willi syndrome, uniparental disomy.
Mitochondrial genetics concerns the diagnosis and management of mitochondrial disorders, which have a molecular basis but result in biochemical abnormalities due to deficient energy production. There exists some overlap between molecular pathology. Genetic counseling is the process of providing information about genetic conditions, diagnostic testing, risks in other family members, within the framework of nondirective counseling. Genetic counselors are non-physician members of the medical genetics team who specialize in family risk assessment and counseling of patients regarding genetic disorders; the precise role of the genetic counselor varies somewhat depending on the disorder. Although genetics has its roots back in the 19th century with the work of the Bohemian monk Gregor Mendel and other pioneering scientists, human genetics emerged later, it started to develop, albeit during the first half of the 20th century. Mendelian inheritance was studied in a number of important disorders such as albinism and hemophilia.
Mathematical approaches were devised
Insulin is a peptide hormone produced by beta cells of the pancreatic islets. It regulates the metabolism of carbohydrates and protein by promoting the absorption of carbohydrates glucose from the blood into liver and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is inhibited by high concentrations of insulin in the blood. Circulating insulin affects the synthesis of proteins in a wide variety of tissues, it is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism of reserve body fat. Beta cells are sensitive to glucose concentrations known as blood sugar levels; when the glucose level is high, the beta cells secrete insulin into the blood. Their neighboring alpha cells, by taking their cues from the beta cells, secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, decreased secretion when glucose concentrations are high.
Glucagon, through stimulating the liver to release glucose by glycogenolysis and gluconeogenesis, has the opposite effect of insulin. The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of glucose homeostasis. If beta cells are destroyed by an autoimmune reaction, insulin can no longer be synthesized or be secreted into the blood; this results in type 1 diabetes mellitus, characterized by abnormally high blood glucose concentrations, generalized body wasting. In type 2 diabetes mellitus the destruction of beta cells is less pronounced than in type 1 diabetes, is not due to an autoimmune process. Instead there is an accumulation of amyloid in the pancreatic islets, which disrupts their anatomy and physiology; the pathogenesis of type 2 diabetes is not well understood but patients exhibit a reduced population of islet beta-cells, reduced secretory function of islet beta-cells that survive, peripheral tissue insulin resistance.
Type 2 diabetes is characterized by high rates of glucagon secretion into the blood which are unaffected by, unresponsive to the concentration of glucose in the blood. Insulin is still secreted into the blood in response to the blood glucose; as a result, the insulin levels when the blood sugar level is normal, are much higher than they are in healthy persons. The human insulin protein is composed of 51 amino acids, has a molecular mass of 5808 Da, it is a dimer of a B-chain, which are linked together by disulfide bonds. Insulin's structure varies between species of animals. Insulin from animal sources differs somewhat in effectiveness from human insulin because of these variations. Porcine insulin is close to the human version, was used to treat type 1 diabetics before human insulin could be produced in large quantities by recombinant DNA technologies; the crystal structure of insulin in the solid state was determined by Dorothy Hodgkin. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.
Insulin may have originated more than a billion years ago. The molecular origins of insulin go at least as far back. Apart from animals, insulin-like proteins are known to exist in the Fungi and Protista kingdoms. Insulin is produced by beta cells of the pancreatic islets in most vertebrates and by the Brockmann body in some teleost fish. Cone snails Conus geographus and Conus tulipa, venomous sea snails that hunt small fish, use modified forms of insulin in their venom cocktails; the insulin toxin, closer in structure to fishes' than to snails' native insulin, slows down the prey fishes by lowering their blood glucose levels. The preproinsulin precursor of insulin is encoded by the INS gene. A variety of mutant alleles with changes in the coding region have been identified. A read-through gene, INS-IGF2, overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. In the pancreatic β cells, glucose is the primary physiological stimulus for the regulation of insulin synthesis.
Insulin is regulated through the transcription factors PDX1, NeuroD1, MafA. PDX1 is in the nuclear periphery upon low blood glucose levels interacting with corepressors HDAC1 and 2, downregulating the insulin secretion. An increase in blood glucose levels causes phosphorylation of PDX1 and it translocates centrally and binds the A3 element within the insulin promoter. Upon translocation it interacts with coactivators HAT p300 and acetyltransferase set 7/9. PDX1 affects the histone modifications through deacetylation as well as methylation, it is said to suppress glucagon. NeuroD1 known as β2, regulates insulin exocytosis in pancreatic β cells by directly inducing the expression of genes involved in exocytosis, it is localized in the cytosol, but in response to high glucose it becomes glycosylated by OGT and/or phosphorylated by ERK, which causes translocation to the nucleus. In the nucleus β2 heterodimerizes with E47, binds to the E1 element of the insulin promoter and recruits co-activator p300 which acetylates β2.
It is able to interact with other transcription factors as well in activation of the insulin gene. MafA is degraded by proteasomes upon low blood glucose levels