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Questions and Answers
What characterizes G-Protein Coupled Receptors (GPCRs)?
How does GTP influence G-Protein activity?
What happens to GPCR signaling when epinephrine concentration decreases?
What is the role of GTPase Activator Proteins (GAPs) in GPCR signaling?
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Which of the following best describes the action of somatostatin in relation to G proteins?
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What is the function of cyclic nucleotide phosphodiesterase in GPCR signaling?
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How does A-Kinase Anchoring Protein (AKAP) contribute to GPCR signaling?
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Which of the following is NOT a type of intercellular signaling discussed?
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What role does somatostatin play in hormone secretion?
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Which mechanism triggers the hyperpolarization of rod or cone cells in vision?
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What happens to G proteins when cholera toxin modifies them?
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How do orexin receptor agonists function in relation to narcolepsy?
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What is the effect of epinephrine on cellular metabolism?
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Which of the following molecules increases cyclic AMP levels in response to olfactory stimuli?
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What physiological effect is associated with the activation of Gs proteins?
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What is the effect of activating GPCRs in gustatory neurons?
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Study Notes
Introduction of Cellular Signaling
- Cells communicate with each other through a variety of mechanisms which include direct contact, signaling molecules, and gap junctions.
- Chemical signals are synthesized by cells and secreted into the extracellular space and act on nearby cells and distant cells.
- Binding to receptors in target cells triggers intracellular signaling pathways that alter cellular processes, including metabolism, gene expression, and cell division.
Properties of Cell Signaling
- The four basic types of cell signaling are:
- Endocrine: Hormones secreted by endocrine cells and distributed throughout the body by bloodstream
- Paracrine: Signaling molecules diffuse locally to nearby target cells.
- Autocrine: Cells release signaling molecules that bind to receptors on their own surface.
- Synaptic: Specialized signaling process that occurs between neurons at synapses.
- The properties that characterize receptor signaling systems are:
- Specificity: Binding of specific signaling molecules to specific receptors
- Amplification: Conversion of a few signaling molecules to produce a large cellular response.
- Desensitization: Decreases the response to repeated stimulus
- Integration: Signaling pathways that are integrated to produce a coordinated cellular response.
Types of Receptors and Signaling Pathways
- Receptors are proteins that bind to signaling molecules and trigger intracellular signaling pathways.
- Receptor types include:
- G Protein-Coupled Receptors (GPCRs): A major class of receptors that are highly diverse in structure and function which interact with G-proteins
G Protein-Coupled Receptor Signaling
- G protein-coupled receptors (GPCRs) are a large family of membrane receptors that are involved in a wide variety of cellular processes.
- GPCRs are characterized by their seven transmembrane α-helical domains and by their association with heterotrimeric G proteins.
- GPCRs can be activated by a variety of stimuli, including hormones, neurotransmitters, and light.
- The activation of GPCRs can lead to the production of second messengers, which regulate various cellular processes.
- There are more than 800 GPCRs in the human genome, making them one of the most diverse families of receptors.
- GPCR signaling pathways are involved in many important physiological processes and functions including allergies, depression, blindness, diabetes, and cancer.
Epinephrine Signaling
- Epinephrine binds to adrenergic receptors on the plasma membrane.
- This binding activates adenyl cyclase, which converts ATP to cyclic AMP (cAMP).
- cAMP activates protein kinase A (PKA), which phosphorylates target proteins, leading to a physiological response.
The GTPase Switch
- The G protein is a heterotrimeric protein composed of three subunits: α, β, and γ.
- In the inactive state, the α subunit binds GDP.
- When a ligand binds to the GPCR, the receptor undergoes a conformational change that allows it to interact with the G protein.
- This interaction causes the α subunit to release GDP and bind GTP.
- The binding of GTP activates the α subunit, which dissociates from the βγ subunits.
- The activated α subunit can then interact with downstream effectors, such as adenyl cyclase.
cAMP as second messenger activates Protein Kinase A
- cAMP activates protein kinase A (PKA), which phosphorylates target proteins.
- PKA activation leads to a variety of physiological responses, depending on the target cells.
- For example, in muscle cells, PKA activation leads to the breakdown of glycogen, providing energy for muscle contraction.
Terminating GPCR Signaling
- The GPCR signaling pathway is terminated by a number of mechanisms, such as:
- The ligand dissociating from the receptor, which causes the receptor to revert to its inactive state.
- GTP hydrolysis, causing the α subunit to dissociate from the effector and re-associate with the βγ subunits.
- Second messenger breakdown, which removes the signal. This is done by enzymes that hydrolyze the second messenger (e.g. phosphodiesterase breaks down cAMP).
- Protein phosphatase activity, which removes phosphate groups from target proteins.
Receptor Desensitization by β-ARK
- β-ARK (β-adrenergic receptor kinase) is a kinase that phosphorylates GPCRs.
- Phosphorylation of GPCRs by β-ARK leads to the recruitment of β-arrestin.
- β-arrestin binds to the phosphorylated GPCR and prevents further activation of the G protein.
- This process of desensitization prevents the cells from becoming overstimulated
Inhibitory G Proteins
- Inhibitory G proteins (Gi) are structurally homologous to Gs but they have a different effect on adenyl cyclase.
- Instead of stimulating adenyl cyclase, Gi inhibits adenyl cyclase and lowers cAMP concentration.
- Tissues with α2 adrenergic receptors – epinephrine lowers cAMP concentration by the inhibitory Gi.
Gq – Coupled Receptor Signaling
- This signaling pathway utilizes G proteins, referred to as Gq.
- This type of signaling pathway regulates the hydrolysis of phosphoinositides, which generates DAG (diacylglycerol) and IP3 (inositol trisphosphate).
- Both of these second messengers trigger different pathways. DAG interacts with protein kinase C, which phosphorylates various substrates, resulting in downstream effects.
- IP3 binds to its receptor on the endoplasmic reticulum (ER), triggering the release of Ca2+ ions, which activate calcium signaling pathways downstream.
Cellular Calcium Signaling
- Calcium ions (Ca2+) are important signaling molecules involved in a variety of cellular processes.
- Ca2+ signaling pathways are regulated by the concentration of calcium in the cytosol.
- Calcium signal pathways have important physiological effects including muscle contraction, neuronal signaling, and secretion.
Protein Regulation by Calmodulin
- Calmodulin (CaM) is a calcium-binding protein that regulates various cellular responses.
- When Ca2+ binds to calmodulin, it undergoes a conformational change that allows it to interact with a variety of target proteins, such as kinases and phosphatases.
- CaM regulates enzyme activity, gene expression, and cytoskeletal rearrangements.
GPCRs in Vision
- In rod and cone cells, light activates rhodopsin, which activates the G protein transducin.
- This activates a phosphodiesterase that hydrolyzes cyclic GMP (cGMP).
- Hydrolysis of cGMP leads to a decrease in the concentration of cGMP and the closing of ion channels in the rod or cone cell plasma membrane, resulting in hyperpolarization.
- The hyperpolarization is the signal that is transmitted to the next neuron in the visual pathway.
- This process is essential for the detection of light and the formation of images by the eye.
GPCRs in Vision, Olfaction and Gustation
- In olfactory neurons, olfactory stimuli, acting through GPCRs and G proteins, trigger an increase in [cAMP] (by activating adenyl cyclase) or [Ca2+] (by activating PLC).
- These second messengers affect ion channels and thus change the membrane potential in olfactory neurons.
- Gustatory neurons have GPCRs that respond to tastants by altering levels of cAMP, which changes the membrane potential by gating ion channels.
GPCR Signaling in Cancer
- GPCRs are expressed in many types of cancer cells and play various roles in cancer development and progression.
- GPCR signaling pathways can influence cell proliferation, survival, migration, and metastasis.
- Many GPCRs can be targets for anticancer drugs and are being actively investigated for their potential in cancer treatment.
Cholera Toxin Mechanism
- The bacterial toxin that causes cholera is an enzyme that catalyzes transfer of the ADP-ribose moiety of NAD+ to an Arg residue of Gs.
- The G proteins thus modified fail to respond to normal hormonal stimuli.
- The pathology of cholera results from defective regulation of adenylyl cyclase and overproduction of cAMP.
Orexin and Sleep Mechanism
- Orexin neuron stimulation is required to maintain wakefulness.
- Narcolepsy is a disorder of the organization of the sleep–wake cycle.
- Narcolepsy patients exhibit excessive daytime sleepiness and cataplexy.
Epinephrine and Synthetic Analogs
- Epinephrine is released from the adrenal gland and regulates energy metabolism.
- It also serves as a neurotransmitter in adrenergic neurons.
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Description
Explore the mechanisms of cellular communication through various signaling types such as endocrine, paracrine, autocrine, and synaptic signaling. This quiz covers the synthesis and action of chemical signals, receptor binding, and the impact on cellular processes. Test your understanding of how cells interact and the pathways involved in these communication methods.
