Molecular Pharmacology: L14-17

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Questions and Answers

Which statement accurately describes the structural characteristics of tyrosine-kinase linked receptors?

They have only one subunit that binds agonists.

They contain a single transmembrane spanning domain. (correct)

They require a pentameric structure for activation.

They consist of multiple transmembrane domains.

What is the primary function of dimerization in signal transduction for tyrosine-kinase linked receptors?

To deactivate the receptor binding sites.

To increase receptor affinity for different ligands.

To activate intrinsic tyrosine kinase activity. (correct)

To initiate apoptosis in the target cell.

Which group of receptors requires ligand binding to initiate signal transduction through dimerization?

G-protein coupled receptors.

Ion channel receptors.

Nuclear hormone receptors.

Tyrosine-kinase linked receptors. (correct)

What type of receptors are steroid receptors, and how do they operate?

They are lipid-soluble receptors that act on intracellular targets. Signup and view all the answers

How does the presence of a ligand affect the structure of tyrosine-kinase linked receptors?

It induces a conformational change that promotes dimerization. Signup and view all the answers

Which method focuses on extracting homologies and shared relationships from sequenced genomes?

Genome data mining Signup and view all the answers

What is the primary purpose of expressed sequence tags (ESTs)?

To assemble random sequences into contiguous sequences Signup and view all the answers

In cDNA screening, which process occurs after purifying the receptor?

Partial amino acid sequencing Signup and view all the answers

What does high stringency in homology screening denote?

High similarity in sequences Signup and view all the answers

Which organisms have been sequenced since 1998 according to the provided content?

Human and Drosophila Signup and view all the answers

What does a cDNA library primarily contain?

Complementary DNA sequences from mRNA Signup and view all the answers

Which type of screening is utilized to find novel receptor sequences?

Low stringency screening Signup and view all the answers

What is a common feature of genome data mining?

Extracting shared genetic relationships Signup and view all the answers

What is the primary aim of the Molecular Pharmacology course described?

To introduce the concept of receptor families Signup and view all the answers

How has genome sequencing contributed to the understanding of receptor families?

It has provided more structural data on receptors. Signup and view all the answers

Which types of receptors are exemplified through the discussion of GPCRs in the course?

Adrenergic receptors and nicotinic acetylcholine receptors Signup and view all the answers

What is one aspect described regarding tyrosine kinases?

They specifically phosphorylate amino acids in proteins. Signup and view all the answers

Which principle is a key focus in the study of pharmacogenomics?

The genetic determinants affecting pharmacodynamics Signup and view all the answers

What did Ahlquist observe regarding adrenergic agonists?

Their potency varies based on the response type. Signup and view all the answers

What distinguishes anatomical classification of receptors?

It refers to distinct responses from different vessels. Signup and view all the answers

What is the relevance of drug affinities and specificities in receptor families?

They help in predicting drug efficacy and response. Signup and view all the answers

Which drug is associated with treating tachycardia?

Propranolol Signup and view all the answers

What is the role of Beta-2 receptors in the airways?

Facilitate asthma relief Signup and view all the answers

Which receptor type is involved in hypertension management through Prazosin?

Alpha-1 Signup and view all the answers

What is a clinical use of Terbutaline?

Management of premature labor Signup and view all the answers

What type of receptor signalling involves G-protein coupled receptors?

Transduction of signal Signup and view all the answers

Which statement describes the role of Alpha-2 receptors?

Inhibit transmitter release Signup and view all the answers

What is the function of receptor tyrosine kinases?

Transducing growth factor signals Signup and view all the answers

Which receptor is linked to enhancing cognitive functions like memory retrieval?

Alpha-2 Signup and view all the answers

What is the predicted secondary structure of G-protein coupled receptors?

Seven transmembrane spanning Signup and view all the answers

Which family of G-protein coupled receptors is associated with biogenic amines?

Family 1a Signup and view all the answers

What happens to the receptor during ligand binding?

It undergoes a conformational change Signup and view all the answers

Which of the following statements about the tertiary structure of GPCRs is correct?

Rhodopsin supports the seven transmembrane model Signup and view all the answers

What is the role of GDP and GTP in G-protein activation?

GTP exchange activates the G-protein Signup and view all the answers

What characteristic might some GPCRs exhibit according to recent evidence?

They may operate as dimers Signup and view all the answers

What type of hormones are associated with Family 1b G-protein coupled receptors?

Peptide hormones Signup and view all the answers

What structural feature is present in the extracellular domain of Family 2 GPCRs?

Bi-lobed structure Signup and view all the answers

What structural form do glutamate receptors take?

Dimers Signup and view all the answers

In the context of the adrenergic receptor, what is the significance of transmembrane helices 5 and 6?

They establish the G-protein binding site upon agonist binding Signup and view all the answers

Which ions do glycine and GABA receptors primarily allow to flow, resulting in an inhibitory effect?

Cl- ions Signup and view all the answers

How are nicotinic acetylcholine receptors categorized in terms of structural composition?

Pentameric functional receptors Signup and view all the answers

What do the broken lines in the model of the beta-1 adrenergic receptor represent?

Weak bonding partners Signup and view all the answers

What role do hydrogen bonds display in the binding of adrenergic agonists to receptors?

They provide structural support for stability Signup and view all the answers

What type of receptor is characterized by a mix of several individual subunits?

Oligomeric receptors Signup and view all the answers

What typically happens when an agonist binds to a GPCR like the beta-1 adrenergic receptor?

It stabilizes conformational changes in the receptor Signup and view all the answers

Study Notes

Molecular Pharmacology 2024 Aims

Introduce the concept of receptor families
Detail how gene cloning and genome sequencing expanded the understanding of receptor families
Describe well-characterized receptor families and their structure-function activities
Use GPCR adrenergic and nicotinic acetylcholine receptors to illustrate how structural information informs about receptor function
Explain the principles of tyrosine kinases and steroid receptors
Introduce the principles of pharmacogenomics
Illustrate how genetic determinants affect drug pharmacokinetics and pharmacodynamics using examples

References

Ritter, et al., 20xx, Rang and Dale's Pharmacology, Chapter 3 and 12, describes drug action and pharmacogenomics respectively.
Corringer, et al.,(2010), provides insights into pentameric ligand-gated ion channels through bacterial homologs
Hockings, et al., (2020), details pharmacogenomics as a clinical tool for precision medicine

IUPHAR Website

The IUPHAR website (https://www.guidetopharmacology.org/) provides a listing of major receptor families
This resource features molecular characteristics, important drugs, their affinities, efficacies and selectivity, and is helpful for revising and drug-related writing tasks

Receptor Families: Classics

Adrenaline/Noradrenaline exhibit diverse effects, having distinct functional consequences for different anatomical tissues/types of vessels.
Categorization exists on the basis of anatomical responses, like contraction and dilatation in blood vessels, and further categorized pharmacologically to classify response potency ranks for adrenergic agonists.
For instance, Noradrenaline, adrenaline, isoprenaline, demonstrating rank-order potency in eliciting constricting vs. dilating responses in anatomical classifications
Classification schemes using these parameters allow more refined understanding and categorization of responses for drug development.

Differential Pharmacology & Receptor Associated Signaling

Agonists like Adrenaline and Noradrenaline have varying effects on receptor sub-types (α-1, α-2, β-1, β-2) based on relative sensitivities.
Drugs like Yohimbine, Propranolol, and Pindolol exhibit specific antagonistic actions that can help understand the functionality of those sub-types of receptors.
This understanding informs further sub-classification based on sensitivity to various stimuli.
Functional classification is facilitated by evaluating responses like +IP3, -cAMP, +cAMP, +cAMP to highlight signaling intricacies

Molecular Classification through Gene Cloning

Identification and sequencing of cDNA for receptors is beneficial.
Amino acid sequencing can be used to classify the receptor subtypes
Comprehensive molecular classification of receptor subtypes is further supported by comparing amino acid sequences

Methods Revealing Receptor Subtypes

The 1980s used protein purification and cDNA cloning techniques to gain new insights into receptor diversity.
1980s to 1990s focused on homology cloning and low-stringency approaches
EST (Expressed Sequence Tags) methods emerged in the 1990s, providing tools for data mining and expanding on receptor family understanding.
More recent work and the ongoing use of genomic data mining facilitates research into more receptor diversity.

Molecular Methods for Understanding Receptor Diversity

cDNA screening (1980s) utilized receptor purification to identify specific partial amino acid sequences to understand their full sequences.
Often these methods have been used with homology screening (1980 and 1990s) that use DNA sequencing
Expressed Sequence Tags (EST) and data mining in the 1990s allowed researchers to isolate specific small sequences (EST) of DNA for deeper information on receptors

Genome Sequencing (1998+)

Genome sequencing has led to an understanding of diverse receptor families (e.g., C. elegans, yeast, human Drosophila, mouse, rat)
Comparative analysis of sequenced genomes is beneficial and allows for the evaluation of known receptors

Building Post-Genomic Receptor Families

cDNA sequences are used to predict protein sequences
Sequence comparison aids in establishing functions and classifying receptors as members of the same family (e.g., G-protein coupled receptors including the adrenoceptors)

Nomenclature of Receptor Types and Subtypes

Organization is hierarchical, from superfamilies to families, subfamilies, sub-types, and sub-classes, leading to a complex classification system.
A good example includes the G-protein coupled receptors (superfamily), which include rhodopsin families and adreno-like receptors that are further classified based on their specifics.

G-protein Coupled Receptor Superfamily

Human genome encodes about 3-5% genes for G-protein-coupled receptors (GPCRs), representing ~ 1000 or more receptors (estimates vary)
Family structures are highlighted alongside receptor types and further receptor family branches
Diverse receptor responses are emphasized, highlighting significant role of genetics in the response to drugs

Tyrosine Kinase-Linked Receptors

These receptors are involved in various growth factors (e.g., NGF) and cellular signal transduction
These receptors have a single transmembrane spanning domain
Tertiary structures encompass isolated ligand-binding domains or kinase domains
Dimerization is commonly associated with their function, and some receptors exist as oligomers

Steroid Receptors

Steroid receptors regulate cell function through intracellular binding with steroid hormones
The structure includes an inactive stage involving HSP-90
Activation leads to detachment from HSP-90 and dimerization facilitating DNA binding.
This process leads to transcription activation of specific genes

Pharmacogenomics

Genetic determinants influence a drug's action in patients
Patient response varies due to genetic variation
Pharmacogenomics aims to tailor treatment by understanding genetic variability
Genetic variability can affect drug metabolism and pharmacokinetics

Principles of Drug Action

Pharmacogenomics explores drug responses impacted by genetic polymorphisms in pharmacokinetics (absorption, distribution, metabolism, excretion) and pharmacodynamics (receptors, ion channels, enzymes, immune system) processes.
No/Little vs Increased responses are influenced by how drug action proceeds through these processes
Varying outcomes in responses are noted.

Genetic Determinants of Biology

Drug responses are often manifested as Mendelian traits with clear inheritance patterns
Genetic variations can alter enzyme activity, such a drug example is succinylcholine used in surgery.
Enzyme activity can impact drug action and response.

High-Throughput Genome Sequencing

This technology reveals genetic variations between individuals, often involving single nucleotide polymorphisms (SNPs)
Variations can include structural variants like insertions, deletions, inversions, and duplications.

Functional Consequences of Genome Variation

Genetic variation can alter gene expression levels, potentially affecting mRNA and ultimately protein production (coding variation and regulatory variation)
Significant examples include receptor regulation impacting response.

Genomic Modulation of Pharmacokinetic Parameters (Cytochrome P450)

Cytochrome P450 enzymes (CYP family) play a major role in drug metabolism, influencing drug action through detoxification and/or activation of drugs.
CYP genes show substantial genetic variation among individuals

Genomic Changes and P450

Genetic variations in CYP genes (deletions, gene duplications/multiplications, and mutations) potentially cause changes in enzyme production, activity, or substrate specificity.
These genetic variations can influence drug metabolism and responses, impacting drug therapy.

Spectrum of Pharmacogenomic Consequences

Extensive metabolizers (EM), ultrarapid metabolizers (UM), intermediate metabolizers (IM), and poor metabolizers (PM) categorize drug metabolism variation
Genetic variation affects drug response, including increased/decreased drug metabolism and potentially narrow therapeutic windows.

Genetic Variation and Drug Targets

Genetic variation can affect drug target molecules such as receptor subtypes and enzyme levels. This can greatly change drug responses.

Modified Signaling and Arg389Gly Beta 1 Receptor

Genetic variations in receptors, such as Arg389Gly in beta-1 receptors, can affect downstream signaling pathways and receptor response
These variations can alter the effectiveness of drugs

Pharmacogenomic Significance and Complexity

Pharmacogenomic factors significantly influence the effectiveness and safety of drug treatment for diseases like heart attacks and hypertension.
Individual variation is a crucial consideration, and clinical trials are important to test these variations in practical settings
A complex web of biological processes necessitates caution and significant consideration for individualized care.

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Description

Explore the essential concepts of molecular pharmacology, including receptor families and the impact of gene cloning on their understanding. This quiz covers structural features and functions of various receptors, pharmacogenomics, and their role in drug response and development. Delve into practical examples to grasp the influence of genetics on pharmacokinetics and pharmacodynamics.