Pathways

Metabolites of Netupitant are predicted with biotransformer.

Neurons are electrically excitable cells that process and transmit information through electrical and chemical signals. A neuron consists of a cell body, branched dendrites to receive sensory information, and a long singular axon to transmit motor information. Signals travel from the axon of one neuron to the dendrite of another via a synapse. Neurons maintain a voltage gradient across their membrane using metabolically driven ion pumps and ion channels for charge-carrying ions, including sodium (Na+), potassium (K+), chloride (Cl−), and calcium (Ca2+). The resting membrane potential (charge) of a neuron is about -70 mV because there is an accumulation of more sodium ions outside the neuron compared to the number of potassium ions inside. If the membrane potential changes by a large enough amount, an electrochemical pulse called an action potential is generated. Stimuli such as pressure, stretch, and chemical transmitters can activate a neuron by causing specific ion-channels to open, changing the membrane potential. During this period, called depolarization, the sodium channels open to allow sodium to rush into the cell which results in the membrane potential to increase. Once the interior of the neuron becomes more positively charged, the sodium channels close and the potassium channels open to allow potassium to move out of the cell to try and restore the resting membrane potential (this stage is called repolarization). There is a period of hyperpolarization after this step because the potassium channels are slow to close, thus allowing more potassium outside the cell than necessary. The resting potential is restored after the sodium-potassium pump works to exchange three sodium ions out per two potassium ions in across the plasma membrane. The action potential travels along the axon and upon reaching the end, causes neurotransmitters such as serotonin, dopamine, or norepinephrine to be released into the synapse. These neurotransmitters diffuse across the synapse and bind to receptors on the target cell, thus propagating the signal.

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.

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.

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.

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.

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.

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.