Browsing Pathways

Gamma-aminobutyric acid (GABA) is an amino acid that serves as the primary inhibitory neurotransmitter in the brain and a major inhibitory neurotransmitter in the spinal cord. It exerts its primary function in the synapse between neurons by binding to post-synaptic GABA receptors which modulate ion channels, hyperpolarizing the cell and inhibiting the transmission of an action potential. The clinical significance of GABA cannot be underestimated. Disorder in GABA signaling is implicated in a multitude of neurologic and psychiatric conditions. Modulation of GABA signaling is the basis of many pharmacologic treatments in neurology, psychiatry, and anesthesia. GABA is synthesized in the cytoplasm of the presynaptic neuron from the precursor glutamate by the enzyme glutamate decarboxylase, an enzyme which uses vitamin B6 (pyridoxine) as a cofactor. After synthesis, it is loaded into synaptic vesicles by the vesicular inhibitory amino acid transporter. SNARE complexes help dock the vesicles into the plasma membrane of the cell. When an action potential reaches the presynaptic cell, voltage-gated calcium channels open and calcium binds to synaptobrevin, which results in the fusion of the vesicle with the plasma membrane and releases GABA into the synaptic cleft where it can bind with GABA receptors. GABA can then be degraded extracellularly or taken back up into glia or the presynaptic cell. It is degraded by GABA-transaminase into succinate semialdehyde which then enters the citric acid cycle. GABA binds to two major post-synaptic receptors, the GABA-A and GABA-B receptors. The GABA-A receptor is an ionotropic receptor that increases chloride ion conductance into the cell in the presence of GABA. The extracellular concentration of chloride is normally much higher than the intracellular concentration. Consequently, the influx of negatively charged chloride ions hyperpolarizes the cell, inhibiting the creation of an action potential. The GABA-B receptor functions via a metabotropic G-protein coupled receptor which increases postsynaptic potassium conductance and decreases presynaptic calcium conductance, which consequently hyperpolarizes the postsynaptic cell and prevents the conduction of an action potential in the presynaptic cell. Consequently, regardless of binding to GABA-A or GABA-B receptors, GABA serves an inhibitory function. GABA is found throughout the human body, though the role that it plays in many regions remains an area of active research. GABA is the primary inhibitory neurotransmitter in the brain, and it is a major inhibitory neurotransmitter in the spinal cord. The insulin-producing beta-cells of the pancreas produce GABA. It functions to inhibit pancreatic alpha cells, stimulate beta-cell growth, and convert alpha-cells to beta cells. GABA also has been found in varying low concentrations within other organ systems, though the significance and function of this are unclear.

Gamma-aminobutyric acid (GABA) is an amino acid that serves as the primary inhibitory neurotransmitter in the brain and a major inhibitory neurotransmitter in the spinal cord. It exerts its primary function in the synapse between neurons by binding to post-synaptic GABA receptors which modulate ion channels, hyperpolarizing the cell and inhibiting the transmission of an action potential. The clinical significance of GABA cannot be underestimated. Disorder in GABA signaling is implicated in a multitude of neurologic and psychiatric conditions. Modulation of GABA signaling is the basis of many pharmacologic treatments in neurology, psychiatry, and anesthesia. GABA is synthesized in the cytoplasm of the presynaptic neuron from the precursor glutamate by the enzyme glutamate decarboxylase, an enzyme which uses vitamin B6 (pyridoxine) as a cofactor. After synthesis, it is loaded into synaptic vesicles by the vesicular inhibitory amino acid transporter. SNARE complexes help dock the vesicles into the plasma membrane of the cell. When an action potential reaches the presynaptic cell, voltage-gated calcium channels open and calcium binds to synaptobrevin, which results in the fusion of the vesicle with the plasma membrane and releases GABA into the synaptic cleft where it can bind with GABA receptors. GABA can then be degraded extracellularly or taken back up into glia or the presynaptic cell. It is degraded by GABA-transaminase into succinate semialdehyde which then enters the citric acid cycle. GABA binds to two major post-synaptic receptors, the GABA-A and GABA-B receptors. The GABA-A receptor is an ionotropic receptor that increases chloride ion conductance into the cell in the presence of GABA. The extracellular concentration of chloride is normally much higher than the intracellular concentration. Consequently, the influx of negatively charged chloride ions hyperpolarizes the cell, inhibiting the creation of an action potential. The GABA-B receptor functions via a metabotropic G-protein coupled receptor which increases postsynaptic potassium conductance and decreases presynaptic calcium conductance, which consequently hyperpolarizes the postsynaptic cell and prevents the conduction of an action potential in the presynaptic cell. Consequently, regardless of binding to GABA-A or GABA-B receptors, GABA serves an inhibitory function. GABA is found throughout the human body, though the role that it plays in many regions remains an area of active research. GABA is the primary inhibitory neurotransmitter in the brain, and it is a major inhibitory neurotransmitter in the spinal cord. The insulin-producing beta-cells of the pancreas produce GABA. It functions to inhibit pancreatic alpha cells, stimulate beta-cell growth, and convert alpha-cells to beta cells. GABA also has been found in varying low concentrations within other organ systems, though the significance and function of this are unclear.

Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatment of heart attacks and unstable angina. It is given intravenously or by injection under the skin.[2] Other uses for its anticoagulant properties include inside blood specimen test tubes and kidney dialysis machines. Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin itself does not break down clots that have already formed (unlike tissue plasminogen activator), it allows the body's natural clot lysis mechanisms to work normally to break down clots that have formed. Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. Heparin binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop. The activated AT then inactivates thrombin, factor Xa and other proteases. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin. The conformational change in AT on heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition, however, thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. The highly negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin. The formation of a ternary complex between AT, thrombin, and heparin results in the inactivation of thrombin. For this reason, heparin's activity against thrombin is size-dependent, with the ternary complex requiring at least 18 saccharide units for efficient formation.

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin ad, "near", and ren, "kidney") is more commonly used in the United Kingdom, whereas "norepinephrine" (from Ancient Greek ἐπῐ́ (epí), "upon", and νεφρός (nephrós), "kidney") is usually preferred in the United States. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic. The general function of norepinephrine is to mobilize the brain and body for action. Norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety. In the rest of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder and gastrointestinal motility. In the brain, noradrenaline is produced in nuclei that are small yet exert powerful effects on other brain areas. The most important of these nuclei is the locus coeruleus, located in the pons. Outside the brain, norepinephrine is used as a neurotransmitter by sympathetic ganglia located near the spinal cord or in the abdomen, as well as Merkel cells located in the skin. It is also released directly into the bloodstream by the adrenal glands. Regardless of how and where it is released, norepinephrine acts on target cells by binding to and activating adrenergic receptors located on the cell surface. Norepinephrine is a catecholamine and a phenethylamine. Its structure differs from that of epinephrine only in that epinephrine has a methyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. Norepinephrine is synthesized from the amino acid tyrosine by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of the sympathetic nervous system. While the conversion of tyrosine to dopamine occurs predominantly in the cytoplasm, the conversion of dopamine to norepinephrine by dopamine β-monooxygenase occurs predominantly inside neurotransmitter vesicles. In mammals, norepinephrine is rapidly degraded to various metabolites. The initial step in the breakdown can be catalyzed by either of the enzymes monoamine oxidase (mainly monoamine oxidase A) or COMT. From there, the breakdown can proceed by a variety of pathways. The principal end products are either Vanillylmandelic acid or a conjugated form of MHPG, both of which are thought to be biologically inactive and are excreted in the urine.[13]

Progesterone is an endogenous steroid hormone that is commonly produced by the adrenal cortex as well as the gonads, which consist of the ovaries and the testes. Progesterone is also secreted by the ovarian corpus luteum during the first ten weeks of pregnancy, followed by the placenta in the later phase of pregnancy. The conversion of progesterone generation from the corpus luteum to the placenta generally occurs after week ten. The molecule progesterone is a derivative of cholesterol and has numerous functions in the human body, especially within the reproductive system. Molecules of progesterone form from the process of steroidogenesis. Progesterone plays a vital role in the maintenance of the uterus during pregnancy. A progestogen (also called progestagen, gestagen, or gestogen) is a molecule, either natural or synthetic, that shows similar effects as progesterone, binds to the progesterone receptor and acts as an agonist. Progestins are synthetic progestogens. Progesterone utilizes intracellular receptors for their mode of action. Progesterone crosses the membrane of a target cell readily by passive diffusion through the plasma membrane due to its lipophilicity and then binds to and activate progesterone receptors. When unbound, the progesterone receptor exists as a monomer. After binding progesterone, the receptor undergoes a conformational change and becomes a dimer, which increases receptor binding to DNA. Most progestins exert their contraceptive effects by suppressing the secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary gland. This suppression alters the menstrual cycle to suppress ovulation. This progesterone and receptor complex then transports to the nucleus and binds to DNA, specifically near the promoter regions of genes that contain enhancers, containing hormone response elements. This binding of the complex to the promoter can either enhance or repress transcription, which ultimately alters the production of proteins.

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. The nicotinic receptors are considered cholinergic receptors, since they respond to acetylcholine. Nicotinic receptors get their name from nicotine which does not stimulate the muscarinic acetylcholine receptors but selectively binds to the nicotinic receptors instead. As ionotropic receptors, nAChRs are directly linked to ion channels. New evidence suggests that these receptors can also use second messengers (as metabotropic receptors do) in some cases. Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors. Opening of the channel allows positively charged ions to move across it; in particular, sodium enters the cell and potassium exits. The net flow of positively charged ions is inward. The nAChR is a non-selective cation channel, meaning that several different positively charged ions can cross through. The activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movement of cations causes a depolarization of the plasma membrane (which results in an excitatory postsynaptic potential in neurons) leading to the activation of voltage-gated ion channels. On the other hand, the entry of calcium acts, either directly or indirectly, on different intracellular cascades. This leads, for example, to the regulation of activity of some genes or the release of neurotransmitters.