Browsing Pathways

Dopamine is a neurotransmitter that can be taken as a tablet for hemodynamic imbalances caused by many heart problems and diseases. Dopamine is a precursor to norepinephrine in the sympathetic nervous system. Dopamine enters the sympathetic neuron through a sodium-dependent dopamine transporter.. In the neuron, it is catalyzed by Dopamine beta-hydroxylase to synthesize norepinephrine. Norepinephrine is stored in synaptic storage sites where norepinephrine was already being stored. When the neuron is depolarized, this accumulation of norepinephrine is released into the synapse. In the synapse, dopamine prevents the re-uptake of norepinephrine by inhibiting Sodium-dependent noradrenaline transporter. The norepinephrine activates Beta-1 adrenergic receptor which is coupled to the G-protein signalling cascade. Activation of the receptor activates the cascade which leads to activated protein kinase through activation of adenylate cyclase. Protein kinase activates calcium channels in the membrane, causing the channels to open and allow Ca2+ into the cell. This causes a high concentration of Ca2+ to be present in the cardiomyocyte which activates activates the ryanodine receptor on the sarcoplasmic reticulum. This transports more Ca2+ into the cytosol. The high concentration of Ca2+ binds to troponin to cause cardiac muscle contractions and therefore, an increased heart rate. This helps conditions like Arrhythmia, myocardial infarctions, open-heart surgery, and trauma-induced hypotension. Dopamine has also been found to increase the amount of circulating epinephrine which can activate the release of norepinephrine in the heart, further increasing heart contractions. Dopamine cannot cross the blood-brain barrier so it is incapable of activating any dopamine receptors in the brain. It can only access the receptors present outside the brain which is why the drug mainly works through norepinephrine in noradrenergic neurons outside the brain, and especially in the heart. Low doses of dopamine cause vasodilation while can help with renal failure and related conditions.

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.

Angiotensin is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex. Aldosterone promotes sodium retention in the distal nephron, in the kidney, which also drives blood pressure up.

using Immunofluorescence for breast cancer

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.

Actions of the neurotransmitter dopamine in the brain are mediated by dopamine receptors that belong to the superfamily of G protein-coupled receptors (GPCRs). Mammals have five dopamine receptor subtypes, D1 through D5. D1 and D5 couple to Gs/olf and activate adenylyl cyclase, whereas D2, D3, and D4 couple to Gi/o and inhibit it. Most GPCRs upon activation by an agonist are phosphorylated by GPCR kinases (GRKs). G protein-coupled receptors (GPCRs) are integral membrane proteins that form the fourth largest superfamily in the human genome. GPCRs were named for their common ability to associate with heterotrimeric G proteins (Gαβγ). The binding of extracellular ligands initiates the signal transduction cascade by triggering conformational changes in the receptor that promote heterotrimeric GTP-binding protein (G protein) activation. The G protein is associated with the plasma membrane at the cytoplasmic side, connecting the GPCR to either enzymes or ion channels. In some cases, G proteins interact with the GPCR before the receptor is activated; in other instances, G protein interacts with GPCR only after stimulation with a ligand. G proteins have three subunits (α,β, and γ). When it is inactive, the α subunit of the G protein is bound to guanosine diphosphate (GDP). However, when a GPCR is activated, it induces the α subunit to release GDP and instead binds to guanosine triphosphate (GTP). By doing so, GPCR acts like a guanine nucleotide exchange factor (GEF). The exchange of GDP with GTP results in a conformational change in the G protein, which leads to its activation. The α subunit of G protein has a GTPase activity, and once it hydrolyzes GTP to GDP, it becomes inactive. The GTPase activity of the α subunit of G protein is significantly enhanced when it interacts with a specific regulator of G protein signaling (RGS). RGS proteins function as subunit-specific GTPase activating proteins (GAPs). There are currently 25 known GAPs in the human genome. GPCRs activate various intracellular signaling, including generating second messengers such as cyclic AMP and inositol phospholipids. GPCRs that stimulate the production of cyclic AMP are often coupled to the stimulatory G protein (Gs), which activates adenylyl cyclase and increases cyclic AMP levels. However, binding an inhibitory G protein (Gi) to a GPCR can inhibit cyclic AMP synthesis.In mammalian cells, GPCR-induced cyclic AMP results in the activation of the cyclic AMP-dependent protein kinase (PKA). Once activated, PKA can phosphorylate many proteins on serine/threonine sites. In the inactive state, PKA is composed of a complex of two catalytic subunits and two regulatory subunits. The binding of cyclic AMP to the regulatory subunits induces a specific conformational change and results in the dissociation of the complex, which leads to the activation of the catalytic subunits. The regulatory subunits of PKA (also known as A-kinase) are important for the sub-cellular localization of PKA, which is facilitated by the interaction of A-kinase anchoring proteins (AKAPs) with the regulatory subunits. One of the well-known targets of PKA is CRE-binding protein (CREB); PKA phosphorylates CREB on a specific serine residue. Phosphorylation of CREB allows the recruitment of a transcriptional co-activator CREB-binding protein (CBP), which stimulates the transcription of various target genes. Many GPCRs elicit their physiological function by activating an inositol phospholipid signaling pathway via phospholipase C-β (PLCβ). This particular pathway is mediated by a sub-class of GPCRs often coupled to a G protein q (Gq) that leads to the activation of PLCβ. Activated PLCβ can hydrolyze phosphoinositol bisphosphate (PIP2) to form 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). While IP3 is known to interact with the IP3 receptors at the endoplasmic reticulum (ER) and results in intracellular calcium release, DAG is best known for its role in the activation of protein kinase C (PKC). In some other cases, GPCRs can directly affect the ion channel activity in the plasma membrane, thereby regulating the ion permeability and membrane potential of the membrane. Yet, other GPCRs can regulate ion channels indirectly by regulating the phosphorylation of signaling proteins such as PKA and PKC.