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.

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.

Gastric acid plays a key role in the digestion of proteins by activating digestive enzymes to break down long chains of amino acids. In addition, it aids in the absorption of certain vitamins and minerals and also acts as one of the body's first line of defence by killing ingested micro-organisms. This digestive fluid is formed in the stomach (specifically by the parietal cells) and is mainly composed of hydrochloric acid (HCl). However, it is also constituted of potassium chloride (KCl) and sodium chloride (NaCl). The main stimulants of acid secretion are histamine, gastrin, and acetylcholine which all, after binding to their respective receptors on the parietal cell membrane, trigger a G-protein signalling cascade that causes the activation of the H+/K+ ATPase proton pump. As a result, hydrogen ions are able to be pumped out of the parietal cell and into the lumen of the stomach. The hydrogen ions are available inside the parietal cell after water and carbon dioxide combine to form carbonic acid(the reaction is catalyzed by the carbonic anhydrase enzyme) which dissociates into a bicarbonate ion and a hydrogen ion. Moreover, the chloride and potassium ions are transported into the stomach lumen through their own channels so that hydrogen ions and/or potassium ions can form an ionic bond with chloride ions to form HCl and/or KCl, which are both constituents of stomach acid. In addition, the peptide hormone somatostatin is the main inhibitor to gastric acid secretion. Not only does it inhibit the G-protein signalling cascade that leads to proton pump activation, but it also directly acts on the enterochromaffin-like cells and G cells to inhibit histamine and gastrin release, respectively.

The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, beta-2 (β2) agonists and alpha-2 (α2) agonists, which are used to treat high blood pressure and asthma, for example. The α2, on the other hand, couples to Gi, which causes a decrease in neurotransmitter release, as well as a decrease of cAMP activity resulting in smooth muscle contraction. Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o (Gi /Go ) family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referred to as Gi alpha, Gαi, or Giα. The general function of Gi/o/z/t is to activate intracellular signaling pathways in response to activation of cell surface G protein-coupled receptors (GPCRs). GPCRs function as part of a three-component system of receptor-transducer-effector. The transducer in this system is a heterotrimeric G protein, composed of three subunits: a Gα protein such as Giα, and a complex of two tightly linked proteins called Gβ and Gγ in a Gβγ complex. When not stimulated by a receptor, Gα is bound to GDP and to Gβγ to form the inactive G protein trimer. When the receptor binds an activating ligand outside the cell (such as a hormone or neurotransmitter), the activated receptor acts as a guanine nucleotide exchange factor to promote GDP release from and GTP binding to Gα, which drives dissociation of GTP-bound Gα from Gβγ. GTP-bound Gα and Gβγ are then freed to activate their respective downstream signaling enzymes. Gi proteins primarily inhibit the cAMP dependent pathway by inhibiting adenylyl cyclase activity, decreasing the production of cAMP from ATP, which, in turn, results in decreased activity of cAMP-dependent protein kinase. Therefore, the ultimate effect of Gi is the inhibition of the cAMP-dependent protein kinase. The Gβγ liberated by activation of Gi and Go proteins is particularly able to activate downstream signaling to effectors such as G protein-coupled inwardly-rectifying potassium channels (GIRKs). Contraction of smooth muscle is initiated by a Ca2+-mediated change in the thick filaments, whereas in striated muscle Ca2+ mediates contraction by changes in the thin filaments. In response to specific stimuli in smooth muscle, the intracellular concentration of Ca2+ increases, and this activator Ca2+ combines with the acidic protein calmodulin. This complex activates MLC kinase to phosphorylate the light chain of myosin (Fig. 1). Cytosolic Ca2+ is increased through Ca2+ release from intracellular stores (sarcoplasmic reticulum) as well as entry from the extracellular space through Ca2+ channels (receptor-operated Ca2+ channels). Agonists (norepinephrine, angiotensin II, endothelin, etc.) binding to serpentine receptors, coupled to a heterotrimeric G protein, stimulate phospholipase C activity. This enzyme is specific for the membrane lipid phosphatidylinositol 4,5-bisphosphate to catalyze the formation of two potent second messengers: inositol trisphosphate (IP3) and diacylglycerol (DG). The binding of IP3 to receptors on the sarcoplasmic reticulum results in the release of Ca2+ into the cytosol. DG, along with Ca2+, activates protein kinase C (PKC), which phosphorylates specific target proteins. There are several isozymes of PKC in smooth muscle, and each has a tissue-specific role (e.g., vascular, uterine, intestinal, etc.). In many cases, PKC has contraction-promoting effects such as phosphorylation of L-type Ca2+ channels or other proteins that regulate cross-bridge cycling.

Dopamine agonists are chemical agents that bind to the dopamine receptors and activate cellular singling pathways. Dopamine receptors classify into two families based on their pharmacological, biochemical, and genetic properties: the D1-like dopamine receptor family includes D1 and D5 receptors, whereas the D2-like dopamine receptor family includes D2, D3, and D4 receptors. All dopamine receptors couple to G proteins. The D1 and D5 receptors couple to the Gs family of G proteins, and therefore an agonist binding to these receptors activate adenylyl cyclase and thus stimulates cAMP synthesis. The D2, D3, and D4 receptors couple to the Gi/o family of G proteins, and agonists inhibit adenylyl cyclase and thus cAMP synthesis. Increased intracellular cAMP activates protein kinase A, which phosphorylates many downstream protein targets, including 32-kDa dopamine and cAMP-regulated phosphoprotein (DARPP-32), ionotropic glutamate receptor, and GABA receptors. Because the DARPP-32 inhibits protein phosphatase 1, this phosphoprotein regulates the phosphorylation state and thus activity of various protein kinase A target proteins and neuronal activity. The D1 receptors are present on the smooth muscle of the renal, mesenteric, and coronary arteries and peripheral blood vessels in the skeletal muscle. Dopamine action on these receptors produces decreased blood pressure by reducing peripheral vascular resistance due to vasodilation. Dopamine agonists used to treat hypertensive emergencies do not show an affinity for D2 receptors.

The M2 muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after negative stimulatory actions of the parasympathetic nervous system, by slowing the speed of depolarization. They also reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of the atrioventricular node (AV node). However, they have little effect on the contractile forces of the ventricular muscle, slightly decreasing force. Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o (Gi /Go ) family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referred to as Gi alpha, Gαi, or Giα. The general function of Gi/o/z/t is to activate intracellular signaling pathways in response to activation of cell surface G protein-coupled receptors (GPCRs). GPCRs function as part of a three-component system of receptor-transducer-effector. The transducer in this system is a heterotrimeric G protein, composed of three subunits: a Gα protein such as Giα, and a complex of two tightly linked proteins called Gβ and Gγ in a Gβγ complex. When not stimulated by a receptor, Gα is bound to GDP and to Gβγ to form the inactive G protein trimer.When the receptor binds an activating ligand outside the cell (such as a hormone or neurotransmitter), the activated receptor acts as a guanine nucleotide exchange factor to promote GDP release from and GTP binding to Gα, which drives dissociation of GTP-bound Gα from Gβγ. GTP-bound Gα and Gβγ are then freed to activate their respective downstream signaling enzymes. Gi proteins primarily inhibit the cAMP dependent pathway by inhibiting adenylyl cyclase activity, decreasing the production of cAMP from ATP, which, in turn, results in decreased activity of cAMP-dependent protein kinase. Inhibition of adenylyl cyclase leads to a decrease in intracellular cAMP levels. In SA node cells, cAMP normally activates protein kinase A (PKA), which phosphorylates If channels, increasing their activity and thereby promoting depolarization. With reduced cAMP levels and decreased PKA activity, If channels become less active. This results in slower and less frequent spontaneous depolarization of SA node cells. Slower depolarization leads to a longer time for the membrane potential to reach the threshold for firing an action potential. In summary, the Gi protein-mediated mechanism in cardiac muscle primarily involves the inhibition of adenylyl cyclase, leading to reduced cAMP levels and decreased PKA activity. This, in turn, inhibits the activity of If channels, which control the rate of spontaneous depolarization in SA node cells. As a result, the heart rate is reduced, allowing the parasympathetic nervous system to exert control over heart rate regulation.

Although numerous GPCRs have the ability to couple to more than one heterotrimeric G protein, a given GPCR is typically classified based on the G protein subfamily (e.g., Gs, Gi/o, or Gq/11) it preferentially activates. Activation of the 5-HT1A receptor typically leads to Gi protein-mediated signaling, which is commonly associated with smooth muscle relaxation rather than contraction. When serotonin (5-HT) or other ligands bind to the 5-HT1A receptor, it triggers a cascade of intracellular events through Gi protein activation. The Gi protein inhibits the activity of adenylate cyclase, which reduces the production of cyclic adenosine monophosphate (cAMP). Reduced cAMP levels can lead to the deactivation of protein kinase A (PKA) and the inhibition of various downstream signaling pathways. In the context of smooth muscle, this reduction in cAMP levels generally leads to smooth muscle relaxation. The physiological effects of serotonin can vary depending on the specific receptors involved, the tissues in question, and the overall context of the signaling pathways. Different serotonin receptors can have opposing effects on smooth muscle, leading to either contraction or relaxation, depending on the receptor subtype and downstream signaling pathways involved. Serotonin increases the motility of the GI tract muscles, induces muscle constriction in the lungs and uterus, influences vessel muscles in both directions (constriction/relaxation), takes part in platelet aggregation, excites nociceptive pain neurons, and influences CNS neurons. Serotonin also plays a role in the symptoms of GI inflammation, acting through different mechanisms to exert pro- or anti-inflammatory activity. Summarily, Gi inhibits adenylate cyclase 5 which results in the reduced conversion of ATP to cAMP and reduced activation of Protein Kinase A (PKA). Lower PKA activity leads to decreased phosphorylation of certain proteins, including myosin light chain (MLC), in smooth muscle cells. Reduced MLC phosphorylation promotes the activation of myosin light chain kinase (MLCK). Activated PKA can phosphorylate calcium activated potassium channels causing potassium efflux and promoting hyperpolarization. Low potassium levels, and the resulting hyperpolarization, can affect the activity of voltage-gated calcium channels. These channels are involved in calcium influx, which can, in turn, influence cAMP levels and PKA activity. Calcium ions can activate adenylate cyclase, leading to increased cAMP production and PKA activation.

Glucocorticoids are a class of steroid hormones that includes cortisol. These hormones bind to specific receptors in cells, called glucocorticoid receptors, which are present in various tissues throughout the body. When cortisol or other glucocorticoids bind to these receptors, they can exert their effects on metabolism, immune function, inflammation, and other physiological processes. The glucocorticoid pathway is essential for regulating these functions and maintaining homeostasis in the body. Cortisol, a steroid hormone, is synthesized from cholesterol. It is synthesized in the zona fasciculata layer of the adrenal cortex. Adrenocorticotropic hormone (ACTH), released from the anterior pituitary, functions to increase LDL receptors and increase the activity of cholesterol desmolase, which converts cholesterol to pregnenolone and is the rate-limiting step of cortisol synthesis. The majority of glucocorticoids circulate in an inactive form, bound to either corticosteroid-binding globulin (CBG) or albumin.[2] The inactive form is converted to its active form by 11-beta-hydroxysteroid dehydrogenase 1 (11-beta-HSD1) in most tissues, while 11-beta-HSD2 inactivates cortisol back to cortisone in the kidney and pancreas. When cortisol binds to the glucocorticoid receptors in the body, it elicits a wide range of physiological and metabolic effects. These effects are part of the body's response to stress and play essential roles in maintaining homeostasis. Major effects that occur naturally are metabolism regulation, wherein Cortisol promotes the breakdown of fats and proteins to provide energy for the body. It also stimulates gluconeogenesis, which is the production of glucose from non-carbohydrate sources, such as amino acids and glycerol. This helps maintain blood glucose levels; anti-inflammatory response wherein cortisol suppresses the immune system's inflammatory response by inhibiting the production of pro-inflammatory cytokines and other mediators of inflammation, immunosuppression wherein cortisol inhibits the activity of immune cells, such as lymphocytes and leukocytes, which can help reduce immune responses. This effect is beneficial in controlling autoimmune reactions but can also make the body more susceptible to infections. Others are stress response and blood pressure regulation, anti-allergic response, tissue repair and modulation of mood and cognitive functions.

las células del epitelio renal pueden captar la glutamina de la sangre, y mediante la enzima glutaminasa, la pueden hidrolizar en NH3 y glutamato. El amoniaco puede pasar al lumen del túbulo. Como la orina es ligeramente ácida, el amoniaco se une a los protones para formar el ion amonio. el glutamato formado por la acción de la glutaminasa se puede desaminar por la glutamato deshidrogenasa generando más NH3 que sale al lumen y α-cetoglutarto. Este metabolito se puede oxidar en la mitocondria completamente generando CO2, que eventualmente generará bicarbonato, mediante la anhidrasa carbónica y la disociación del H2CO3.