Biochemical Signaling - Biochemistry

Epinephrine and glucagon are examples of hormones that affect G protein-coupled receptors like adenylate cyclase and increase levels of cAMP. The other hormones listed affect receptor tyrosine kinases and non-receptor tyrosine kinases.

Elevated arginine leads to an increase in secretion of insulin, not decreased. GIP, CCK and closing of the voltage gated potassium channels lead to an increase in secretion of insulin.

Glucagon is released in a fasted or high-stress state (including increased concentration of blood cortisol or epinephrine). It is also induced when blood insulin levels are decreased. Recall that glucagon and insulin have antagonistic functions, and are thus secreted in opposite temporal patterns.

The observed increase in diacylglycerol (DAG) is indicative of the activation of a GProtein-Coupled Receptor (GPCR).

Upon binding of a ligand to a GPCR, a conformational change in the receptor is transmitted to a G protein bound to the cell membrane within the cell. This subsequently causes the alpha-subunit of the G protein to lose its bound GDP, and in exchange it receives GTP. This, in turn, activates the G protein, causing the alpha subunit to dissociate from the beta-gamma subunit. This newly liberated alpha subunit-GTP complex then goes on to activate another component of the signal transduction cascade. There are two main types of GPCR signaling pathways, depending on the type of alpha subunit involved.

cAMP Pathway: When the alpha subunit is stimulatory, denoted as , it will activate an enzyme in the plama membrane called adenylyl cylcase. Activation of this enzyme results in the conversion of ATP into cAMP. cAMP, in turn, acts as a second messenger within the cell, activing Protein Kinase A (PKA). This protein kinase then goes on to phosphorylate several proteins within the cell, which leads to a response. Furthermore, the G protein may also be inhibitory and denoted as . This alpha subunit essentially does the opposite of what does. That is, it acts to inhibit adenylyl cyclase, with a subsequent decrease in intracellular levels of cAMP and a reduction in the activity of PKA.

Phosphatidylinositol Pathway: In this case, the G protein is denoted as . This particular G protein goes on to activate an enzyme called phospholipase C (PLC). PLC, in turn, cleaves a certain phospholipid within the plasma membrane called phosphatidylinositol-4,5-bisphosphate () into two products, inositol-1,4,5-trisphosphate () and diacylglycerol (DAG). dissociates from the membrane and binds to a receptor on the endoplasmic reticulum, stimulating the release of into the cytosol. Together, DAG and work together to activate Protein Kinase C (PKC), which then goes on to phosphorylate many proteins within the cell, leading to a cellular response.

And briefly, receptor tyrosine kinases (RTK) are receptors located in the plasma membrane. Upon binding its ligand, RTK's have two intracellular domains that phosphorylate each other, thus activating the receptor. The RTK then goes on to trigger a signal transduction cascade.

Ionotropic receptors are located in the plasma membrane, and they also serve as ion channels through which ions can flow. Generally, binding of ligand to ionotropic receptors induces a conformational change in the receptor that causes the ion channel to open.

The dihydropyridine receptor (DHP) is located in the plasma membrane and is generally associated with another receptor known as the ryanodine receptor, located in the membrane of the endoplasmic reticulum. Generally, the DHP receptor is activated by a change in membrane voltage, and upon stimulation causes: 1) an influx of from the extracellular fluid into the cytosol, and 2) is mechanically coupled to the ryanodine receptor, stimulating it to release from the endoplasmic reticulum into the cytoplasm.

And finally, as the name implies, intracellular receptors are not located in the plasma membrane, but instead located in either the cytosol or nucleus. For a ligand to bind this class of receptor, it must be able to diffuse across the plasma membrane to make its way into the cell. Generally, upon activation, intracellular receptor-ligand complexes act as transcription factors, directly modulating the activity of certain genes by altering their expression.

G protein-coupled receptors contain nine seven transmembrane alpha helices. All other statements are true of G protein-coupled receptors.

Phospholipase C catalyses the formation of DAG (diacylglycerol) and IP3 (inositol triphosphate) from PIP2 (phosphatidylinositol-4,5-bisphosphate). IP3 promotes the influx of calcium ions into the cytoplasm while DAG stimulates protein kinase C.

Ketone bodies, which include acetoacetate, beta-hydroxybutyrate, and acetone, are produced by the liver in the fasting state by beta-oxidation of fatty acids. They are then released into the blood stream, where they can be used as alternative energy sources for other organs, such as muscle, kidney, and brain. Apoprotein B is one of the proteins that hold lipoproteins together. Beta-carotene is a vitamin with antioxidant properties.

Out of all the neurotransmitters listed, the only one that isn't a catecholamine is serotonin. This neurotransmitter is initially derived from the amino acid tryptophan, whereas the catecholamines are derived from the amino acid tyrosine.

Dopamine, norepinephrine, and epinephrine are all catecholamine neurotransmitters. In fact, in the metabolic pathway that produces these compounds, dopamine is an intermediate that can be converted into norepinephrine, which can subsequently be converted into epinephrine.

Tyrosine hydroxylase is the rate-limiting enzyme for catecholamine synthesis. It catalyzes the conversion of tyrosine to dihydroxy-phenylalanine (DOPA). Tryptophan hydroxylase is the rate-limiting step for serotonin synthesis. Dopamine beta-hydroxylase converts dopamine to norepinephrine. Amino acid decarboxylase converted DOPA to dopamine.

Chromaffin cells are located in the adrenal gland, and release epinephrine and norepinephrin.

Chromaffin cells release both epinephrine and norepinephrine, but 80% of the neurotransmitters released is epinephrine.

Epinephrine first binds to an adrenergic receptor. The activated receptor works via a G protein, and so GDP is exchanged for GTP and the protein is activated. This then causes activation of adenylate cyclase and subsequent conversion of ATP to cAMP. cAMP acts upon protein kinase A and several other effector molecules. Diacylglycerol and IP3 are second messengers that are uninvolved in this process.

Of the options given, only norepinephrine is synthesized in storage vesicles. The rest are synthesized in cytoplasm.

Dihydroxyphenylalanine (DOPA) is the precursor for dopamine. Of the options, only dopamine, epinephrine, and norepinephrine are released upon nerve firing.

Erythropoietin is a glycoprotein hormone produced in the kidney that stimulates the production of red blood cells in the bone marrow.

Glucagon is a short peptide hormone involved in triggering signal cascades in response to low blood glucose. Biotin, also known as vitamin B7, is a cofactor in fatty acid synthesis. Pyridoxal phosphate, the activated form of vitamin B6, is a cofactor in transamination reactions, among others. Epinephrine is a steroid hormone involved in the fight or flight response.

Tyrosine hydroxylase is the rate-limiting enzyme for all catecholamine synthesis reactions. L-aromatic amino acid decarboxylase is needed to catalyze the step from DOPA to dopamine. Norepinephrine synthesis requires dopamine beta-hydroxylase and epinephrine synthesis requires dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase (PNMT) in addition to the other enzymes mentioned.

NETs are used to remove norepinephrine from the synaptic cleft. Tryptophan hydroxylase and amino acid decarboxylase are part of the serotonin synthesis pathway. VMA is a breakdown product of norepinephrine.

Parkinson disease is associated with decreased dopamine concentration. It is commonly treated with L-DOPA, which can cross the blood brain barrier and be converted to dopamine.