4.1: GPCR Coupling Selectivity in Neuronal Signaling
G-protein-coupled receptors (GPCRs) play a crucial role in neuronal signaling, where they modulate various aspects of neurotransmission and synaptic plasticity. GPCR coupling selectivity is essential in this context, as it enables specific GPCRs to selectively interact with particular downstream effectors, thereby fine-tuning the neuronal response. In this sub-chapter, we will discuss several examples of GPCRs and their effects on neuronal signaling.
One such example is the metabotropic glutamate receptors (mGluRs), a family of GPCRs that modulate glutamatergic neurotransmission. There are eight mGluR subtypes, which are classified into three groups based on their sequence homology, pharmacological properties, and signal transduction mechanisms. Group I mGluRs (mGluR1 and mGluR5) primarily couple to G~q/11~ proteins, leading to the activation of phospholipase C (PLC) and the production of diacylglycerol (DAG) and inositol trisphosphate (IP3). These second messengers, in turn, activate protein kinase C (PKC) and mobilize intracellular calcium, respectively, thereby modulating synaptic plasticity and neurotransmitter release. In contrast, Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR6-8) mGluRs predominantly couple to G~i/o~ proteins, inhibiting adenylyl cyclase (AC) and reducing cyclic adenosine monophosphate (cAMP) levels. These GPCRs also modulate potassium channels, leading to hyperpolarization and reduced neuronal excitability.
Another example of GPCR coupling selectivity in neuronal signaling is the dopamine receptors, which belong to the D1-like (D1 and D5) and D2-like (D2, D3, and D4) families. D1-like receptors primarily couple to G~s/olf~ proteins, activating AC and increasing cAMP levels, while D2-like receptors predominantly interact with G~i/o~ proteins, inhibiting AC and reducing cAMP levels. These differential coupling properties have significant implications for dopamine-mediated neuronal signaling, as they underlie the distinct functional roles of these receptors in various brain regions, such as the striatum, prefrontal cortex, and hippocampus.
In summary, GPCR coupling selectivity is crucial for modulating neuronal signaling, as it enables specific GPCRs to interact with particular downstream effectors, thereby fine-tuning the neuronal response. Examples of GPCRs that exhibit coupling selectivity in neuronal signaling include metabotropic glutamate receptors and dopamine receptors.
Key points:
- GPCR coupling selectivity is essential for modulating neuronal signaling.
- Metabotropic glutamate receptors exhibit coupling selectivity, with Group I mGluRs activating PLC and Group II/III mGluRs inhibiting AC.
- Dopamine receptors also display coupling selectivity, with D1-like receptors activating AC and D2-like receptors inhibiting AC.
4.2: GPCR Coupling Selectivity in the Cardiovascular System
GPCR coupling selectivity is also critical in the cardiovascular system, where specific GPCR-effector interactions regulate heart rate, blood pressure, and vascular tone. In this sub-chapter, we will discuss several examples of GPCRs and their effects on the cardiovascular system.
One such example is the β-adrenergic receptors (β-ARs), which are GPCRs that modulate cardiac function in response to catecholamines such as adrenaline and noradrenaline. There are three β-AR subtypes (β1, β2, and β3), which display differential coupling selectivity. β1-ARs primarily couple to G~s~ proteins, activating AC and increasing cAMP levels, while β2-ARs predominantly interact with G~s~ and G~i/o~ proteins, activating AC and inhibiting AC, respectively. β3-ARs, on the other hand, primarily couple to G~i/o~ proteins, inhibiting AC and reducing cAMP levels. These differential coupling properties have significant implications for cardiac function, as they underlie the distinct functional roles of these receptors in regulating heart rate, contractility, and metabolism.
Another example of GPCR coupling selectivity in the cardiovascular system is the angiotensin II receptors (AT1R and AT2R), which are GPCRs that modulate blood pressure and vascular tone in response to the renin-angiotensin system. AT1R primarily couples to G~q/11~ proteins, activating PLC and increasing DAG and IP3 levels, while AT2R predominantly interacts with G~i/o~ proteins, inhibiting AC and reducing cAMP levels. These differential coupling properties have significant implications for cardiovascular function, as they underlie the distinct functional roles of these receptors in regulating blood pressure, vascular tone, and inflammation.
In summary, GPCR coupling selectivity is crucial for modulating cardiovascular function, as it enables specific GPCRs to interact with particular downstream effectors, thereby fine-tuning the cardiovascular response. Examples of GPCRs that exhibit coupling selectivity in the cardiovascular system include β-adrenergic receptors and angiotensin II receptors.
Key points:
- GPCR coupling selectivity is essential for modulating cardiovascular function.
- β-adrenergic receptors exhibit coupling selectivity, with β1-ARs activating AC and β2/β3-ARs inhibiting AC.
- Angiotensin II receptors also display coupling selectivity, with AT1R activating PLC and AT2R inhibiting AC.
4.3: GPCR Coupling Selectivity in Immune Response
GPCR coupling selectivity is also critical in the immune response, where specific GPCR-effector interactions modulate immune cell functions, such as chemotaxis, phagocytosis, and cytokine production. In this sub-chapter, we will discuss several examples of GPCRs and their effects on the immune response.
One such example is the chemokine receptors, which are GPCRs that mediate chemotaxis, the directed migration of immune cells towards sites of inflammation or injury. Chemokine receptors exhibit coupling selectivity, with some receptors primarily coupling to G~i/o~ proteins, inhibiting AC and reducing cAMP levels, while others predominantly interact with G~q/11~ proteins, activating PLC and increasing DAG and IP3 levels. These differential coupling properties have significant implications for immune cell function, as they underlie the distinct functional roles of these receptors in regulating immune cell migration and activation.
Another example of GPCR coupling selectivity in the immune response is the histamine receptors, which are GPCRs that modulate allergic responses and inflammation. There are four histamine receptor subtypes (H1-H4), which display differential coupling selectivity. H1 and H2 receptors primarily couple to G~q/11~ and G~s~ proteins, respectively, activating PLC and AC, while H3 and H4 receptors predominantly interact with G~i/o~ proteins, inhibiting AC and reducing cAMP levels. These differential coupling properties have significant implications for histamine-mediated immune responses, as they underlie the distinct functional roles of these receptors in regulating allergic reactions, inflammation, and neurotransmission.
In summary, GPCR coupling selectivity is crucial for modulating immune function, as it enables specific GPCRs to interact with particular downstream effectors, thereby fine-tuning the immune response. Examples of GPCRs that exhibit coupling selectivity in the immune response include chemokine receptors and histamine receptors.
Key points:
- GPCR coupling selectivity is essential for modulating immune function.
- Chemokine receptors exhibit coupling selectivity, with some receptors activating PLC and others inhibiting AC.
- Histamine receptors also display coupling selectivity, with H1 and H2 receptors activating PLC and AC, respectively, and H3 and H4 receptors inhibiting AC.
4.4: GPCR Coupling Selectivity in Gastrointestinal System
GPCR coupling selectivity is also critical in the gastrointestinal system, where specific GPCR-effector interactions regulate motility, secretion, and nutrient absorption. In this sub-chapter, we will discuss several examples of GPCRs and their effects on the gastrointestinal system.
One such example is the motilin receptors, which are GPCRs that modulate gastric motility and emptying. Motilin receptors primarily couple to G~q/11~ proteins, activating PLC and increasing DAG and IP3 levels, thereby stimulating gastric motility and emptying. These coupling properties have significant implications for gastrointestinal function, as they underlie the distinct functional roles of these receptors in regulating gastric emptying and motility.
Another example of GPCR coupling selectivity in the gastrointestinal system is the secretin receptors, which are GPCRs that modulate pancreatic secretion and bicarbonate production. Secretin receptors primarily couple to G~s~ proteins, activating AC and increasing cAMP levels, thereby stimulating pancreatic secretion and bicarbonate production. These coupling properties have significant implications for gastrointestinal function, as they underlie the distinct functional roles of these receptors in regulating pancreatic secretion and bicarbonate production.
In summary, GPCR coupling selectivity is crucial for modulating gastrointestinal function, as it enables specific GPCRs to interact with particular downstream effectors, thereby fine-tuning the gastrointestinal response. Examples of GPCRs that exhibit coupling selectivity in the gastrointestinal system include motilin receptors and secretin receptors.
Key points:
- GPCR coupling selectivity is essential for modulating gastrointestinal function.
- Motilin receptors exhibit coupling selectivity, activating PLC and stimulating gastric motility and emptying.
- Secretin receptors also display coupling selectivity, activating AC and stimulating pancreatic secretion and bicarbonate production.