Pathways

Holocarboxylase synthetase deficiency also called Multiple Carboxylase Deficiency, Neonatal or Early Onset Form, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of either mutations in the BTD gene or the HLCS gene. The BTD gene encodes for biotinidase and the HLCS gene encodes for holocarboxylase synthetase. This disorder is classified as a multiple carboxylase deficiency, a group of disorders characterized by impaired activity of enzymes dependent on biotin. Symptoms of holocarboxylase synthetase deficiency typically appear within the first few months of life, and include difficulty feeding, breathing problems, a skin rash, hair loss, and lethargy. Treatment using biotin supplements if immediate and lifelong can be effective in preventing many complications and managing the disorder. However, if left untreated the disorder can lead to delayed development, seizures, and coma.

Holocarboxylase synthetase deficiency also called Multiple Carboxylase Deficiency, Neonatal or Early Onset Form, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of either mutations in the BTD gene or the HLCS gene. The BTD gene encodes for biotinidase and the HLCS gene encodes for holocarboxylase synthetase. This disorder is classified as a multiple carboxylase deficiency, a group of disorders characterized by impaired activity of enzymes dependent on biotin. Symptoms of holocarboxylase synthetase deficiency typically appear within the first few months of life, and include difficulty feeding, breathing problems, a skin rash, hair loss, and lethargy. Treatment using biotin supplements if immediate and lifelong can be effective in preventing many complications and managing the disorder. However, if left untreated the disorder can lead to delayed development, seizures, and coma.

Holocarboxylase synthetase deficiency also called Multiple Carboxylase Deficiency, Neonatal or Early Onset Form, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of either mutations in the BTD gene or the HLCS gene. The BTD gene encodes for biotinidase and the HLCS gene encodes for holocarboxylase synthetase. This disorder is classified as a multiple carboxylase deficiency, a group of disorders characterized by impaired activity of enzymes dependent on biotin. Symptoms of holocarboxylase synthetase deficiency typically appear within the first few months of life, and include difficulty feeding, breathing problems, a skin rash, hair loss, and lethargy. Treatment using biotin supplements if immediate and lifelong can be effective in preventing many complications and managing the disorder. However, if left untreated the disorder can lead to delayed development, seizures, and coma.

Tubular striated muscle cells (i.e. skeletal and cardiac myocytes) are composed of bundles of rod-like myofibrils. Each individual myofibril consists of many repeating units called sarcomeres. These functional units, in turn, are composed of many alternating actin and mysoin protein filaments that produce muscle contraction. The muscle contraction process is initiated when the muscle cell is depolarized enough for an action potential to occur. When acetylcholine is released from the motor neuron axon terminals that are adjacent to the muscle cells, it binds to receptors on the sarcolemma (muscle cell membrane), causing nicotinic acetylcholine receptors to be activated and the sodium/potassium channels to be opened. The fast influx of sodium and slow efflux of potassium through the channel causes depolarization. The resulting action potential that is generated travels along the sarcolemma and down the T-tubule, activating the L-type voltage-dependent calcium channels on the sarcolemma and ryanodine receptors on the sarcoplasmic reticulum. When these are activated, it triggers the release of calcium ions from the sarcoplasmic reticulum into the cytosol. From there, the calcium ions bind to the protein troponin which displaces the tropomysoin filaments from the binding sites on the actin filaments. This allows for myosin filaments to be able to bind to the actin. According to the Sliding Filament Theory, the myosin heads that have an ADP and phosphate attached binds to the actin, forming a cross-bridge. Once attached, the myosin performs a powerstroke which slides the actin filaments together. The ATP and phosphate are dislodged during this process. However, ATP now binds to the myosin head, which causes the myosin to detach from the actin. The cycle repeats once the attached ATP dissociates into ADP and phosphate, and the myosin performs another powerstroke, bringing the actin filaments even closer together. Numerous actin filaments being pulled together simultaneously across many muscles cells triggers muscle contraction.

Tubular striated muscle cells (i.e. skeletal and cardiac myocytes) are composed of bundles of rod-like myofibrils. Each individual myofibril consists of many repeating units called sarcomeres. These functional units, in turn, are composed of many alternating actin and mysoin protein filaments that produce muscle contraction. The muscle contraction process is initiated when the muscle cell is depolarized enough for an action potential to occur. When acetylcholine is released from the motor neuron axon terminals that are adjacent to the muscle cells, it binds to receptors on the sarcolemma (muscle cell membrane), causing nicotinic acetylcholine receptors to be activated and the sodium/potassium channels to be opened. The fast influx of sodium and slow efflux of potassium through the channel causes depolarization. The resulting action potential that is generated travels along the sarcolemma and down the T-tubule, activating the L-type voltage-dependent calcium channels on the sarcolemma and ryanodine receptors on the sarcoplasmic reticulum. When these are activated, it triggers the release of calcium ions from the sarcoplasmic reticulum into the cytosol. From there, the calcium ions bind to the protein troponin which displaces the tropomysoin filaments from the binding sites on the actin filaments. This allows for myosin filaments to be able to bind to the actin. According to the Sliding Filament Theory, the myosin heads that have an ADP and phosphate attached binds to the actin, forming a cross-bridge. Once attached, the myosin performs a powerstroke which slides the actin filaments together. The ATP and phosphate are dislodged during this process. However, ATP now binds to the myosin head, which causes the myosin to detach from the actin. The cycle repeats once the attached ATP dissociates into ADP and phosphate, and the myosin performs another powerstroke, bringing the actin filaments even closer together. Numerous actin filaments being pulled together simultaneously across many muscles cells triggers muscle contraction.

Tubular striated muscle cells (i.e. skeletal and cardiac myocytes) are composed of bundles of rod-like myofibrils. Each individual myofibril consists of many repeating units called sarcomeres. These functional units, in turn, are composed of many alternating actin and mysoin protein filaments that produce muscle contraction. The muscle contraction process is initiated when the muscle cell is depolarized enough for an action potential to occur. When acetylcholine is released from the motor neuron axon terminals that are adjacent to the muscle cells, it binds to receptors on the sarcolemma (muscle cell membrane), causing nicotinic acetylcholine receptors to be activated and the sodium/potassium channels to be opened. The fast influx of sodium and slow efflux of potassium through the channel causes depolarization. The resulting action potential that is generated travels along the sarcolemma and down the T-tubule, activating the L-type voltage-dependent calcium channels on the sarcolemma and ryanodine receptors on the sarcoplasmic reticulum. When these are activated, it triggers the release of calcium ions from the sarcoplasmic reticulum into the cytosol. From there, the calcium ions bind to the protein troponin which displaces the tropomysoin filaments from the binding sites on the actin filaments. This allows for myosin filaments to be able to bind to the actin. According to the Sliding Filament Theory, the myosin heads that have an ADP and phosphate attached binds to the actin, forming a cross-bridge. Once attached, the myosin performs a powerstroke which slides the actin filaments together. The ATP and phosphate are dislodged during this process. However, ATP now binds to the myosin head, which causes the myosin to detach from the actin. The cycle repeats once the attached ATP dissociates into ADP and phosphate, and the myosin performs another powerstroke, bringing the actin filaments even closer together. Numerous actin filaments being pulled together simultaneously across many muscles cells triggers muscle contraction.

Muscle contractions occur when the myocyte is depolarized enough for an action potential to occur. Depolarization is caused by acetylcholine released from the adjacent motor neuron, which activates nicotinic acetylcholine receptors and opens the sodium/potassium channel. The fast influx of sodium and slow efflux of potassion trigger the action potential. This action potential activates L-type voltage-dependent calcium channels on the membrane and ryanodine receptors on the sarcoplasmic reticulum, both which cause calcium ions to be released into the cytosol. In smooth muscle, ionic calcium induces muscle contraction by binding to and activating myosin light chain kinase, while in striated muscle contraction results from ionic calcium binding to and activating troponin C.

G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases. Heterotrimeric G proteins located within the cell are activated by G protein-coupled receptors (GPCRs) that span the cell membrane. Signaling molecules bind to a domain of the GPCR located outside the cell, and an intracellular GPCR domain then in turn activates a particular G protein. Some active-state GPCRs have also been shown to be "pre-coupled" with G proteins, whereas in other cases a collision coupling mechanism is thought to occur. The G protein triggers a cascade of further signaling events that finally results in a change in cell function. G protein-coupled receptors and G proteins working together transmit signals from many hormones, neurotransmitters, and other signaling factors. G proteins regulate metabolic enzymes, ion channels, transporter proteins, and other parts of the cell machinery, controlling transcription, motility, contractility, and secretion, which in turn regulate diverse systemic functions such as embryonic development, learning and memory, and homeostasis. Receptor-activated G proteins are bound to the inner surface of the cell membrane. They consist of the Gα and the tightly associated Gβγ subunits. There are four main families of Gα subunits: Gαs (G stimulatory), Gαi (G inhibitory), Gαq/11, and Gα12/13. They behave differently in the recognition of the effector molecule, but share a similar mechanism of activation. When a ligand activates the G protein-coupled receptor, it induces a conformational change in the receptor that allows the receptor to function as a guanine nucleotide exchange factor (GEF) that exchanges GDP for GTP. The GTP (or GDP) is bound to the Gα subunit in the traditional view of heterotrimeric GPCR activation. This exchange triggers the dissociation of the Gα subunit (which is bound to GTP) from the Gβγ dimer and the receptor as a whole. Both Gα-GTP and Gβγ can then activate different signaling cascades (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein. 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. 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). Gi and Go proteins are substrates for pertussis toxin, produced by Bordetella pertussis, the infectious agent in whooping cough. Pertussis toxin is an ADP-ribosylase enzyme that adds an ADP-ribose moiety to a particular cysteine residue in Giα and Goα proteins, preventing their coupling to and activation by GPCRs, thus turning off Gi and Go cell signaling pathways. Activation of Gi proteins in vascular smooth muscle cells often results in vasoconstriction. This is because reduced cAMP levels and decreased PKA activity lead to increased intracellular calcium concentrations, promoting smooth muscle contraction. In summary, while Gi signaling plays a role in both smooth and cardiac muscle tissues, its specific effects and functions differ due to the distinct roles and regulatory mechanisms of these muscles. In smooth muscle, Gi signaling often leads to vasoconstriction, while in cardiac muscle, it primarily regulates heart rate through the inhibition of If channels in the SA node, resulting in a negative chronotropic effect.