GPCRs and RTKs Overview

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Questions and Answers

What structural feature is common among all GPCR families?

Three intracellular loops (correct)

Five distinct family sequences

A single transmembrane helix

An extracellular ligand binding domain

Which family of receptors is NOT part of the GPCR superfamily?

Rhodopsin

Receptor Tyrosine Kinases (correct)

Adhesion

Glutamate

What is one of the primary roles of receptor tyrosine kinases (RTKs)?

Control cell growth and motility (correct)

Enhance ligand dissociation

Mediate enzyme activation

Facilitate apoptosis exclusively

What occurs when a ligand dissociates from its receptor?

It terminates the signalling process Signup and view all the answers

What kind of signaling pathways are GPCRs involved in?

Both G protein-dependent and G protein-independent pathways Signup and view all the answers

Retosiban is known for its role as which type of drug?

An oxytocin receptor antagonist Signup and view all the answers

Why do different tissues respond uniquely to signal molecules?

Expression of different receptors in various tissues Signup and view all the answers

What percentage of proteins coded in the human genome are estimated to be plasma membrane receptors?

5% Signup and view all the answers

What occurs when a charged substance is translocated without moving an opposite charge?

S’1 S’2 electrogenic transport Signup and view all the answers

Which transport mechanism involves moving two or more species in the same direction?

Symport Signup and view all the answers

What is the role of the electrochemical-potential gradient in transport mechanisms?

To drive the movement of molecules Signup and view all the answers

Which of the following describes transporters that cannot create a concentration gradient across membranes?

Facilitated diffusion Signup and view all the answers

When does a transport mechanism become classified as electrically silent?

When two molecules of the same charge are moved in opposite directions Signup and view all the answers

Which transport mechanism involves the transport of a single solute?

Uniport Signup and view all the answers

What defines the antiport mechanism in transport?

Two solutes moving in opposite directions Signup and view all the answers

What is common to all electrochemical-potential-driven transporters?

They utilize an electrochemical-potential gradient Signup and view all the answers

What occurs when acetylcholine binds to the nicotinic-acetylcholine receptor?

The receptor opens, allowing Na+ to flow into the cell. Signup and view all the answers

Which ion's permeability is reduced in patients with Cystic Fibrosis (CF)?

Cl- Signup and view all the answers

What is the role of phosphorylation in the regulation of CFTR?

Phosphorylation activates the CFTR channel. Signup and view all the answers

What effect do antagonists have on ligand-regulated channels?

They inhibit the channel's function. Signup and view all the answers

Which type of channel allows for the rapid passage of ion flow, essential for nerve conduction?

Ligand-gated channels Signup and view all the answers

What kind of agents are used to enhance the activity of ligand-gated channels?

Agonists Signup and view all the answers

How do neurotoxins affect the nicotinic-acetylcholine receptor?

They inhibit the receptor, blocking ion flow. Signup and view all the answers

What primarily confirms the diagnosis of Cystic Fibrosis in a patient?

Significantly increased Cl- content of sweat. Signup and view all the answers

Which condition is NOT associated with increased AQP2 levels leading to extracellular fluid volume expansion?

Dehydration Signup and view all the answers

How does nephrogenic diabetes insipidus primarily affect urine output?

Causes low levels of AQP2 and polyuria Signup and view all the answers

What is the transport rate comparison between channels and specific transporters?

Channels operate at approximately $10^7$ ions/s Signup and view all the answers

What defines the movement mechanism of transporter proteins?

They bind the solute, change conformation, and move the substrate across the membrane Signup and view all the answers

What deficiency is indicated by individuals lacking AQPl activity?

They have no issues but may struggle under hydration stress Signup and view all the answers

Which statement best describes pores and channels in membrane transport?

They include an aqueous pore that controls molecular movement Signup and view all the answers

What is a common characteristic of transport proteins based on their classification?

They exhibit structural homology within subfamilies Signup and view all the answers

Which of the following ions is NOT mentioned as an influence in the context of aquaporin function?

Sodium (Na+) Signup and view all the answers

What mechanism is primarily responsible for the transport of glucose across the plasma membranes of mammalian cells?

Passive uniport mechanism Signup and view all the answers

Which type of ATPase is responsible for transporting Ca2+ back into the endoplasmic reticulum?

P-type transporters Signup and view all the answers

What is the role of the Na+ independent Cl- - HCO3- exchanger?

To adjust the HCO3- concentration in erythrocytes Signup and view all the answers

In which condition is there a defect in the sodium-coupled glucose-galactose transporter?

Decreased glucose uptake from the intestinal tract Signup and view all the answers

What type of transport mechanism do glucose and amino acids utilize together with Na+?

Symport mechanism Signup and view all the answers

What condition results from a decrease in the transport of neutral amino acids?

Harnup disease Signup and view all the answers

Which of the following is specifically responsible for the abnormal renal reabsorption of cystine and basic amino acids?

Cystine and basic amino acids transporter Signup and view all the answers

In hypophosphatemic, vitamin D – resistant rickets, which type of absorption is abnormal?

Phosphate absorption Signup and view all the answers

Study Notes

GPCRs

Form a superfamily of membrane proteins with five distinct families
All share common structural motifs: seven transmembrane (TM) helices connected to three extracellular loops and three intracellular loops.
Have unique combinations of signal-transduction activities involving G protein-dependent and G protein-independent signaling pathways.

Receptor Tyrosine Kinases (RTKs)

A subclass of tyrosine kinases involved in cell-to-cell communication and controlling various biological functions such as cell growth, motility, differentiation, and metabolism.
58 known RTKs in humans, all share a similar protein structure with an extracellular ligand binding domain, a single transmembrane helix, and an intracellular region containing a juxtamembrane regulatory region, a tyrosine kinase domain (TKD), and a carboxyl (C-) terminal tail.

Receptor Binding

Binding of a signal molecule to its receptor is an equilibrium process, similar to substrate binding in enzymes, but most cases involve no chemical modification of the bound ligand.
Receptors are excellent targets for pharmaceuticals.

Oxytocin Receptor Antagonist

Retosiban (GSK-221,149-A) is an oral drug that acts as an oxytocin receptor antagonist.
Blocks oxytocin-mediated uterine smooth muscle contraction during preterm labor, preventing preterm labor and premature birth.

Membrane Transport Proteins

A functional classification system by the International Union of Biochemistry and Molecular Biology (IUBMB) categorizes them into classes, subclasses, families, and subfamilies based on transport mechanism and properties.
Many are present in prokaryotes and both prokaryotes and eukaryotes, including mammals.
Structural homology exists among proteins in many subfamilies.

Pores and Channels

Contain an aqueous pore through which molecules diffuse; movement is controlled by a gating mechanism.

Transporter Proteins

Similar to enzymes, they bind the solute on one side of the membrane, change conformation, and move the substrate to the opposite side.

Characteristics of Pores/Channels and Transporters

Most have a high degree of solute specificity.
Substrate translocation rate is higher in channels (about 10 7 ions/ s) than in specific transporters (about 10 2 - 10 3 molecules/s).

Ligand-Regulated Channels

Respond to binding of specific extracellular or intracellular chemical ligands (agonists), leading to channel opening or closing.
For example, acetylcholine binding to the nicotinic-acetylcholine receptor opens the channel, allowing Na+ flow into the cell, crucial for neuronal electrical signal transmission.
Neurotransmitters, cAMP, inositol l,4,5-trisphosphate, diacylglycerol, and G proteins can control other channels.
Fast channel opening allows rapid bursts of ion flow (10 7 ions per second), essential for nerve conduction and muscle contraction.

Nerve Terminal Surface

Contains various channels, including voltage-dependent channels for Ca2+, K+, Ca2+-gated K+ channels, ligand-gated channels, and stretch-activated channels.

Neurotoxins and Channel Inhibition

Neurotoxins such as d-tubocurarine (curare's active ingredient) and snake toxins like a-bungarotoxin, erabutoxin, and cobratoxin inhibit the nicotinic-acetylcholine receptor.
Succinylcholine, a muscle relaxant, opens the channel leading to membrane depolarization, used in surgeries due to its reversible activity after administration.

Channel Regulation

Ligand binding and phosphorylation-dephosphorylation can control some channels.
Pharmacological agents can modulate channels, inhibitors are antagonists.

Cystic Fibrosis (CF)

CF patients have decreased Cl- permeability, impairing fluid and electrolyte secretion causing dehydration.
Diagnosis is confirmed by significantly increased Cl- content in sweat.
CF gene product is the cystic fibrosis transmembrane conductance regulator (CFTR ), a cAMP-dependent Cl- channel expressed in epithelial tissues and may regulate other ion channels.
Phosphorylation by protein kinase A activates the channel.

Membrane Transport Protein Systems

Some systems move two substrates in one direction and two substrates in opposite directions.
Translocation of a charged substance without movement of an opposite charge or translocation of two molecules with different charges creates charge separation across the membrane, termed S’1 S’2 electrogenic transport, leading to membrane potential development.
Movement of an oppositely charged ion to neutralize or moving two molecules of the same charge in opposite directions is termed neutral or electrically silent transport.

Electrochemical-potential Driven Transporters

Uniport mechanism: transports a single solute by mediated diffusion or in a membrane-potential-dependent manner for charged solutes.
Antiport mechanism: transports two or more solutes in opposite directions in a tightly coupled process without using energy other than the electrochemical-potential gradient. The gradient of one solute can drive the movement of the other.
Symport mechanism: transports two or more species together in the same direction in a coupled process without using energy other than the electrochemical-potential gradient of one substrate.

Uniport Mechanism

Involves transporting molecules down their chemical gradient (for uncharged molecules) or down an electrochemical gradient (for charged molecules). This is often referred to as protein-mediated diffusion or facilitated diffusion.
These transporters cannot create a concentration gradient across the membrane.

Symport and Antiport Mechanisms

Movement down a concentration gradient of one solute can drive the translocation of the other molecule.
These are referred to as secondary active transporters, distinguished from primary active transporters.

Ca2+ Active Transport

Two distinct Ca2+ -transporting ATPases (Ca2+ -ATPases) reestablish low cytosolic Ca2+ levels: one transporting Ca2+ back into the endoplasmic or sarcoplasmic reticulum lumen and the other out of the cell across the plasma membrane.
Ca2+ -ATPases are P-type transporters, phosphorylated by ATP on an aspartyl residue.

Glucose Translocation

Facilitated by a family of glucose transporters (GLUT ) through a uniport mechanism across mammalian cell plasma membranes.

Symport Mechanism for Glucose and Amino Acids

Na+ driven transport of d-glucose, with two Na+ moving into the cell down their electrochemical gradient by passive facilitated transport and glucose carried along against its concentration gradient.

Antiport Mechanism for Cl- and HCO 3-

An anion transporter in erythrocytes and kidneys mediates the electroneutral antiport movement of Cl- and HCO 3-.
This transporter is referred to as the Na+ independent Cl-- HCO3 - exchanger or anion exchange protein.
Important in adjusting erythrocyte HCO 3- concentration in arterial and venous blood.
The kidney transporter is a truncated form of the erythrocyte protein responsible for base (HCO 3-) efflux to balance ATP-driven H+ efflux.

Diseases due to Loss of Membrane Transport Systems

Individuals with decreased intestinal glucose uptake lack the specific sodium-coupled glucose-galactose transporter.
Fructose malabsorption syndromes are caused by altered fructose transport system activity.
Harnup disease involves decreased transport of neutral amino acids in intestinal and renal epithelial cells.
Cystinuria has abnormal renal reabsorption of cystine and basic amino acids lysine, arginine, and ornithine, leading to renal cystine stones.
Hypophosphatemic, vitamin D – resistant rickets involves abnormal renal phosphate absorption.
Genetic diseases involving substrate transporters for dopamine and creatine, and the mitochondrial aspartate glutamate transporter have also been reported.

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Explore the fascinating world of G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). This quiz covers their structures, functions, and signaling mechanisms in detail. Test your knowledge on these crucial components of cell communication.