Browsing Pathways

Citalopram is a selective serotonin reuptake inhibitor that exerts antidepressive effects by selectively inhibiting serotonin reuptake in the brain. It does so by competing for the same binding site as serotonin on the the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of serotonin in the synaptic cleft and reverses the state of low concentration seen in depression. Higher concentration of serotonin has also been shown to have long-term neuromodulatory effects. Binding of serotonin to certain serotonin receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.

Repaglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, repaglinide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Repaglinide stimulate insulin secretion in a glucose-sensitive manner by inhibiting ATP-dependent potassium channels. As a result, there tends to be a lesser likelihood of hypoglycemia with repaglinide therapy compared to sulfonylureas.

Prednisone is a medication that is used to suppress the immune system. It works by interrupting cytokine pathways type 1 and type 2. It is administered orally, through tablet, or solution (concentrated or non-concentrated). Prednisone is a glucocorticoid, and as well as being used for immune system suppression, it is used for its anti inflammatory properties. It exerts these properties by binding to glucocorticoid receptors in the cell, which inhibits inflammatory cells. This prevents inflammatory mediators from being expressed.

In the nervous system, dopamine acts as a neurotransmitter with roles in motor control, motivation, arousal, cognition, and reward. The mesolimbic pathway is the main pathway associated with reward, and the dopaminergic neurons of this pathway are found in the substantia nigra (SNc) and ventral tegmental area (VTA) of the midbrain. Dopamine acts on different G protein-coupled receptor subtyes. The D1-class (D1 and D5) receptors stimulate cAMP production by activating adenylyl cyclase, which activates the reward pathway. The D2-class (D2, D3, and D4) subtypes act oppositely, inhibiting cAMP production by inhibiting adenylyl cyclase. The differing distributions of the receptor subtypes mean that complex outputs often produce a synergistic effect, despite the receptor subtypes having opposite molecular effects (PMID: 20925949, 21303898).

A member of the G-coupled protein receptor family, the adenosine A2A receptor regulates blood flow to myocardial tissues through the action of vasodilating the coronary arteries, which can potentially lead to hypotension. The adenosine receptor A2a activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response. This occurs through activation of the MAPK/ERK signaling cascade. The A2A receptor has also been demonstrated to play a role in dopamine and glutamate release in the CNS.

Cyclooxygenase is the major producer of prostacyclin. Prostacyclin binding to its receptor increases vasodilation and decreases platelet aggregation. The receptor is a G-protein coupled receptor, upon its binding it activates G proteins causing the activation of adenylyl cyclase and production of cAMP messenger molecules. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.In vasodilation, the PKA activity causes phosphorylation of MLCK, decreasing its activity, resulting in dephosphorylation of MLC of myosin. This leads to smooth muscle relaxation resulting in vasodilation.

BH4-deficient hyperphenylalaninemia has several causes. One such cause is a PTS deficiency resultant from a genetic mutation. (In particular, a mutation in the gene encoding 6-pyruvoyl-tetrahydropterin synthase.) The mutation is autosomal recessive. Common symptoms include: muscular hypotonia, ataxia, bradykinesia, choreoathetosis, depressivity, dysphagia, hyperkinesis, hypsarrhythmia, myoclonus, and others. BH4 is a cofactor involved in many things and associated with neurotransmitter synthesis. In short, the reduction of levels of BH4 creates issues in the metabolism of phenylalanine. This cascade of reactions produces the aforementioned symptoms.

Carnosinemia, also known as carnosinemia, is a rare inborn error of metabolism (IEM) and recessive autosomal disorder caused by a defective CNDP1 gene which encodes for carnosinase. Carnosinase is a dipeptidase enzyme that catalyzes the breakdown of Carnosine into alanine and histidine. This disorder is characterized by secretion of large amounts of carnosine and anserine in the urine but low levels of methylhistidine. Patients also have unusually high concentrations of homocarnosine in the cerebrospinal fluid. Other symptoms include progressive neurologic disorders characterized by severe mental defect and myoclonic seizures. There is no known cure for Carnosinemia therefore treatment involves management of symptoms. There have been about 30 cases of Carnosinemia reported worldwide.

Galactokinase deficiency also called Galactosemia type II, is a rare inborn error of metabolism (IEM) and an autosomal recessive disorder of galactokinase caused by a mutation in the GALK1 gene on chromosome 17q24. Galactokinase uses 1 ATP to catalyse the phosphorylation of α-D-galactose to galactose 1-phosphate and catalyses β-D-galactose to glucose 1-phosphate. Symptoms include cataract formation in children who are exposed to lactose in their diets. Cataract formation is the result of osmotic phenomena caused by the accumulation of galactitol in the lens. Treatment includes immediately removing lactose from patient’s diet, however symptoms such as delayed speech, cognitive learning and motor skills can still be present.

5-Oxoprolinase deficiency, also called OPLAHD, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of glutathione metabolism caused by a defective 5-oxoprolinase. 5-Oxoprolinase catalyzes the conversion of 5-oxoproline into glutamate which is an important neurotransmitter. This disorder is characterized by a large accumulation of 5-oxoproline in the urine. Symptoms of the disorder include enterocolitis, mental retardation, kidney stone formation, and hypoglycemia. 5-Oxoprolinase deficiency has been reported in approximately 8 people.