Browsing Pathways

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.

Gq protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gq/11 (Gq/G11) family or Gq/11/14/15 family to include closely related family members. G alpha subunits may be referred to as Gq alpha, Gαq, or Gqα. Gq proteins couple to G protein-coupled receptors to activate beta-type phospholipase C (PLC-β) enzymes. PLC-β in turn hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacyl glycerol (DAG) and inositol trisphosphate (IP3). IP3 acts as a second messenger to release stored calcium into the cytoplasm, while DAG acts as a second messenger that activates protein kinase C (PKC). Depending on the Gα subunit involved in the complex, the most well-known G-proteins are qualified as Gi, Gs, or Gq. They signal through different pathways. Gq proteins rely on enzymes of the phospholipase C family (PLC), while Gs and Gi proteins respectively stimulate and inhibit adenylate cyclase (AC) and thus act upon the amount of cytosolic cAMP. 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. Adrenergic receptors that use Gq protein signalling to contract smooth muscles include the alpha-1 receptors. The alpha-1 receptor agonist actions include Smooth muscle contraction, mydriasis, vasoconstriction in the skin, mucosa and abdominal viscera & sphincter contraction of the GI tract and urinary bladder.

Insulin is a peptide hormone secreted in the body by beta cells of islets of Langerhans of the pancreas and regulates blood glucose levels. Medical treatment with insulin is indicated when there is inadequate production or increased insulin demands in the body. Insulin is responsible for the regulation of glucose levels in the body. It stimulates the storage of energy and inhibits the breakdown of high energy metabolites. Insulin acts by directly binding to its receptors on the plasma membranes of the cells. These receptors are present on all the cells, but their density depends on the type of cells, with the maximum density being on the hepatic cells and adipocytes. The insulin receptor is a heterotetrameric glycoprotein consisting of two subunits, the alpha and the beta subunits. The extracellular alpha subunits have insulin binding sites. The beta subunits, which are transmembranous, have tyrosine kinase activity. When insulin binds to the alpha subunits, it activates the tyrosine kinase activity in the beta subunit, which causes the translocation of glucose transporters from the cytoplasm to the cell's surface. Insulin promotes glycogen synthesis, lipid synthesis, protein synthesis, DNA synthesis, and cellular growth and differentiation. Once glucose gets absorbed from a meal, it enters the blood, and then the pancreas releases insulin. Insulin synthesis occurs in the beta cells of the pancreas initially as preproinsulin. Preproinsulin then converts to proinsulin, which then transforms into a single peptide with A, B, and C peptide units. The A and B peptides are joined by disulfide bonds to make insulin and are secreted into the bloodstream. Insulin binds to its cellular receptor. The insulin receptor is composed of alpha subunits, beta subunits, and a tyrosine kinase enzyme. When insulin binds to the alpha subunit, this triggers phosphorylation and activation of the target proteins intracellularly by the tyrosine kinase leading to many effects on cellular metabolism. Activation of the insulin receptor also leads to increased expression of GLUT (a glucose transporter) to the membrane surface and promotes the entry of glucose to the intracellular compartment and then undergoes cellular metabolism. Insulin signals glucose conversion to glycogen for storage and the formation of acetyl coenzyme A and triacylglycerol, which get stored in adipose tissue. Also, insulin directs amino acids for protein synthesis. Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5′ flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox-1(PDX-1), MafA, and B-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion.

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 is a digestive fluid, formed in the stomach. Gastric acid is produced by cells lining the stomach, which are coupled to systems to increase acid production when needed.