Communication and Coordination: Cell Signaling LOOK AT FIGURE 11.16
Clicker questions:
Increasing active Gs ________adenylyl cyclase activity. Increases
Increasing cAMP _____protein kinase a activity. Increases
In the inactive state, _____ is bound to the ______ subunit of a G protein. GDP, alpha
G protein found in the retina, associated with vision. Gt
Second Messenger—cAMP and Calcium
Hormones that work antagonistically…work against each other.
Steroid hormones bind to…intracellular receptors
One chemical first messenger can elicit different effects—true
To regulate blood sugar use: two hormones working antagonistically
After eating a big bowl of ice cream, your calcium levels are: elevated
Your PTH levels after were: lowered
How is a G protein turned off? GTP is hydrolyzed to GDP
Each cell type expresses a single type of receptor. False
Each first messenger binds to a single type of receptor. False
What is the consequence of Gi not interacting with receptors? cAMP levels will not decrease
What happens if the GTPase activity of the alpha subunit increases due to a mutation? Cell signal terminates prematurely and the first messenger is not amplified as strongly.
A ligand is a small molecule, which binds to a receptor or … True
Paracrine signaling occurs…over short distances
First messenger: hormone
A G protein coupled receptor has how many alpha helices spanning the plasma membrane? 7
Which G protein subunit has an intrinsic GTPase activity? Alpha
An example of long-distance signaling: hormonal
Example of homeostasis: Constant body temp, constant pH and constant ion concentration.
Increasing active Gs _____ adenylyl cyclase activity. Increases
Increasing cAMP _______protein kinase a activity. Increases
In the inactive state, what is bound to what subunit of a G protein? GDP, alpha
G protein found in the retina, associated with vision. Gt
Second messenger: cAMP and Calcium
Steroid hormones bind to: intracellular receptors
Neurotransmitters are ______messengers. First
What is the distribution of sodium ions? (Low) intracellular
All cells have a membrane potential. True
All cells are excitable. False
How do you depolarize a cell? Open sodium channels (positive charges into the cell to make cell less negative)
One chemical first messenger can elicit different effects. True

Cell communication * Coordinate metabolic processes * Receive messages from both local and distant sources * The messenger is a chemical signal * Respond to the signal through a change in the metabolic processes of the cell

An extracellular chemical signal * Is transduced into an intracellular response * Change in biochemical reactions that occur within the cell * Communication occurs across the plasma membrane * Extracellular signal is amplified within the cell via a signaling cascade

Local Signaling * Paracrine—Diffusion of “first messengers” over short distance between cells * Synaptic—Chemical signals from a nerve axon diffuse across a synapse to another nerve cell or a muscle cell

Long-distance Signaling * Hormonal Signaling * Endocrine (ductless) glands produce chemicals (hormones) * Hormones move through the circulatory system to their targets

Communication by direct contact between cells * Gap junctions in animal cells * Plasmodesmata between plant cells * Cell recognition through surface receptors

Cell Signaling * An extracellular chemical messenger * The extracellular first messenger is transduced (transformed) into an intracellular chemical messenger. * Second messenger * Elicits a metabolic change within the cell * May involve a receptor in the plasma membrane * An integral membrane protein—penetrate completely through the membrane * May involve an intracellular receptor (inside the cell) * E.g., steroid hormone receptors * Cell amplification and how does it benefit the cell? * Amplify faint signal * A few “first messenger” molecules * Many second messenger molecules * Each step in the cascade recruits more molecules * Elicit a coordinated response * What is the role of phosphorylation cascades in signal amplification * Activated kinase activiates a ____?

G protein—coupled signaling (pick up off “final” notes) * Important class of signaling complexes * More than 1,000 different types of G-protein coupled receptors in a mammal * Coupling = receptors interact with G-protein * Guanine-nucleotide-binding proteins (G proteins) * Link an extracellular signal and intracellular response * Three Components * Receptor in the plasma membrane * G protein on the intracellular (internal) face of the plasma membrane * “Effector” element such as an enzyme or ion channel

Membrane receptors * Over 1000 G protein coupled receptors (GPCRs) * Integral membrane protein with 7 alpha helical regions spanning the membrane (heptahelical) * Amino terminus extracellular 5212q * Carboxy terminus intracellular * Activated by binding of a “first” messenger signal molecule * Hormone * Neurotransmitter * Interacts with a G protein

Heterotrimeric G protein * 3 different subunits labeled: alpha, beta, gamma * Interacts with receptor occupied by a signaling molecule. * When activated interacts with an effector element * Associated with the intracellular (internal) face of the plasma membrane

Effector enzyme (e.g., adenylyl cyclase) * Produces an intracellular “second” messenger. * Adenylyl cyclase is an integral membrane protein
Another example of an effector element: * Ion channel—controls movement of ions across the plasma membrane (down concentration gradient)

G protein –coupled signal transduction system components * Membrane receptor—G protein—adenylyl cyclase

GPCR (G Protein Coupled Receptor) * Activated by the binding of a “first” messenger signal molecule * Hormone * Neurotransmitter * Interacts with a G protein

Examples of G-proteins * Gs—stimulatory G protein * Stimulates adenylyl cyclase * Increases activity of adenylyl cyclase * Gi—inhibitory G protein * Inhibits adenylyl cyclase * Golf—olfactory G protein * Gt—transducin, the G protein involved in vision
G proteins * “Switch” protein * Either “on” or “off” * Activated by occupied (activated) receptor * Consists of three different subunits (αβγ) * GDP is bound to the α subunit of the inactive G protein heterotrimer * GDP or GTP binds to the nucleotides * Inactive (“off”) α—GDPβγ * Active (“on”): α—GTP +βγ * GTP replaces the GDP and causes a change in the protein * Alpha subunit with GTP bound and a beta gamma dimer * A G protein is turned off when GTP is hydrolyzed to GDP.
Activation of G proteins * An activated receptor interacts with the G protein * GTP replaces GDP on the alpha subunit * The G protein dissociates intoα -GTP and a βγ dimer. * The G protein is now “on”

Activated G protein * Interacts with target enzymes or ion channels
Inactivating G proteins: * Turned “off” when an intrinsic GTPase activity of the alpha subunit hydrolyzed GTP to GDP * Alpha-GDP and the beta gamma dimer reassociate * Now everything is ready to go again

G-protein signaling—couple signaling * Membrane receptor is activated by an extracellular signal * G protein transfers the extracellular signal into the intracellular compartment by interacting with a target. * Target enzyme produces a “second Messenger”

First messenger * Hormones
Second Messenger * Cyclic adenosine monophosphate (cAMP) * Synthensized from ATP * Activates an enzyme called protein kinase * Calcium * Muscle contractions

Adenylyl Cyclase * Produces cAMP from ATP * The enzyme is modulated (positively and negatively) by different G proteins * Intracellular cAMP levels go up or down * Depends on the summation of all the positive and negative signals on that cell. cAMP * Activates an enzyme called protein kinase

Signaling Components * Membrane receptor—>G protein—>adenylyl cyclase—>cAMP—>protein kinase A

(CELL SIGNALING) Protein Kinase and phosphorylation reactions—enzyme that phosphorylates target proteins * Covalent transfer of phosphate group from ATP to specific amino acids of target protein * Known as post-translational modification * Protein has been produced and now the protein kinase puts a phosphate group on a specific amino acid. * Phosphorylation * Acts as an “on” or “off” switch for the target protein * Can be reserved by a protein phosphatase
Protein Kinase A—R2C2 * Inactive kinase –4subunits (a tetramer) * 2 regulatory subunits * 2 catalytic subunits * Activating Protein Kinase A * In the cytoplasm cAMP binds to the R subunit * R2C2 dissociates into an R dimer and 2 C monomers * When activated, release 2 active subunits * C monomers can catalyze phosphorylation reactions

Protein Phosphatase: The Phosphorylation of proteins can be reversed by enzymes called protein phosphatase. * These enzymes remove the covalent bound phosphate groups

Phosphorylation—Acts as an ‘on’ or ‘off’ switch for the target position * Can be reversed by a phosphatase

Phosphorylation “cascade” FIGURE 11.10 * Activated kinase activates a different kinase, etc. * At each step, more enzymes are recruited.

Anaerobic burst metabolism * Powered by glycolysis * Quickly mobilized * Increased rate of glycolysis in a fraction of a second * Increased enzyme activity due to a phosphorylation cascade * Can also be triggered by calcium (activate phosphorylase kinase)

Examples of cellular responses to first messengers * Glycogen breakdown * Protein synthesis

Signaling Cascade (know what a sig. cascade is and what it does—went into detail all the way before Incactive protein kinase A) * Amplify faint signal * A few “first messenger” molecules * Many second messenger molecules * Elicit a coordinated response * Amplifying the signal * Each step in the cascade recruits more molecules

G protein and receptor defects and diseases * Loss of function mutations: preclude formation of stable mRNA or protein * Gain of function mutations: e.g., activation of receptor in the absence of agonist * Defect in rhodopsin (vision)—retinitis pigmentosa
E.G., Bacterial Toxins (didn’t go over) * Pertussis Toxin (PTX) * Prevents Gi from interacting with receptors * Botulinum Toxin (BTX, Botox) * Inhibits GTPase activity of Gs

Another type of Kinase * Tyrosine Kinase * Phosphorylates specific tyrosine’s in the target. * (Protein kinase A phosphorylates the amino acids serine and threonine)

A ligand is a small molecule that binds to a receptor or enzyme.

Ligand-gated ion channel (didn’t go over) * Ion channel controls movement of ions across a membrane * The channel is open/closed (gated) by extracellular signal molecules which bind to the channel

Paracrine signaling occurs over short distances

Activation of protein synthesis by an extracellular first messenger * First messenger—growth factor * A signaling cascade of phosphorylation events activates transcription in the nucleus

Long distance Signaling—Hormones (first messengers)
Animals
Endocrine System: * Regulatory system that maintains homeostasis through hormones. * Consists of hormone and the glands (endocrine glands =ductless glands), which secrete them. * Endocrine glands secrete hormones into the circulation
Homeostasis—steady-state physiological condition * Constancy of the interior environment of an organism * E.g., constant intracellular pH, body temperature, ion concentrations * To maintain homeostasis
Hormones
* Worksheet on Moodle * Regulatory chemical * Produced in an endocrine gland * Secreted into the blood and carried to target cells * Extracellular “first” messengers

Target Cells * Respond to hormone by altering their metabolism * Have receptors for specific first messengers * Different cell types will have a different profile of receptors

Regulation * Results from function of the endocrine system and the nervous system. * Ex: specialized neurosecretory cells secrete hormones * Homeostasis is achieved through feedback mechanisms

Amines * Hormones that are derived from the amino acids tyrosine and tryptophan * Ex: epinephrine, thyroxine, and serotonin

Polypeptides—short chain of amino acids that are covalently linked * E.g., insulin, glucagon, antidiuretic hormone, oxytocin

Glycoproteins—carbohydrate groups that are covalently linked * E.g., FSH, LH, and TSH

Steroids * Hydrophobic and therefore require Intracellular receptors * Cycling between the cytoplasmic and nuclear compartments * Activated receptor in the nucleus activates specific genes by binding to DNA * Effects: * Increased protein synthesis * Slow onset due to this * E.g., glucocorticosteroids—cortisol * E.g., mineralocorticoids—aldosterone * E.g., mineralocorticoid—aldosterone

Acetylcholine receptors * 2 different types of receptor for the same compound * Nicotinic—(nicotine binds) they can interact with nicotine, found in heart muscle * Muscarinic—(muscarine binds) can interact with a compound isolated by mushrooms, found in skeletal muscle * Different types of receptors for the same hormone elicit different responses * Found on different cells, in different tissues

Pancreas * Insulin (peptide hormone) * 140 amino acids long * Lowers blood glucose level * Diabetes—inability to regulate blood glucose levels * Type I (Insulin-dependent) * Childhood onset * Autoimmune destruction of cells releasing insulin because immune system destroys the beta cells that create insulin. * Inability to produce insulin * Type II (Insulin-independent) * Adult onset (40 years +) * Recently seen more frequently in children * Failure of the signal transduction system to elicit a response to insulin or inadequate insulin production * Insulin-independent because of the failure of signal transduction system to cause a response of the cells that stimulate the production of insulin. * Onset related to obesity and heredity * Glucagon (increase in blood glucose level) work antagonistically * Also a peptide hormone * Release from alpha cells in pancreas and raises blood glucose levels

Osteocalcin * Produced by cells in bones * Hormone that influences energy metabolism * Affects pancreatic and fat cells—prevents them from growing * Skeleton affects energy metabolism * Affects testosterone production in males via a GPCR * Produced by bones * Affects energy metabolism * Affects bone remodeling * Affects testosterone production in males

Thyroid Gland * T3 (Triiodothyonine) & T4 (Thyroxine) * Amines that stimulate and maintain metabolism * Bind to intracellular receptors

Feedback Control * Regulation of secretion of thyroid hormones

Feedback regulation of calcium …

Calcium homeostasis (know the figure, chap 45) * Calcitonin * Peptide hormone * Produced in thyroid gland * Lowers blood calcium levels * Parathyroid Hormone (PTH) * Peptide hormone * Produced in the parathyroid gland * Raises blood calcium levels
Bone
* Bone matrix—collagen principal component * Calcium phosphate * Bone is continuously being remodeled * Osteoporosis * Particular problem in elderly women * Age-related alteration in bone homeostasis * Can also result form glucocorticoid administration * Estrogens important in prevention of postmenopausal osteoporosis * Though to act by opposing the calcium-mobilizing, bone-reabsorbing effect of PTH

Hormones soluble in Lipids
Stress and Steroid Hormones * Increased production of epinephrine and norepinephrine * Adrenal medulla * Increased production of mineralo- and gluco- coriticoids (steroids) * Adrenal cortex * Figure 25.21

Short-term stress response * Glycogen broken down, blood glucose increased. * Increased blood pressure and breathing rate * Increased metabolic rate * Change in blood flow decreasing digestive and kidney activity

Long-term stress effects * Mineralocorticoids * Cause the retention of sodium and water * Results in increased blood volume and blood pressure * Glucocorticoids * Result in breakdown of proteins and fats to increase blood glucose * Suppression of the immune system, decreasing ability of organism to respond to things like bacteria

Ligands for steroid receptors * Steroid hormones * Thyroid hormones (T3 and T4) * Vitamin D * Retinoic Acid

Steroid Effect * Produced by steroids increasing protein synthesis * Slow in onset due to this

Testes * Steroids produce androgens, e.g., testosterone * Support sperm formation; male secondary sex characteristics

Ovaries * Steroids produce estrogens * Stimulate uterine lining growth * Development and maintenance of female secondary sex characteristics

Neurons Worksheet on Moodle
Neurons—
* Cell body: * Contains the nucleus and organelles * Clusters of cell bodies are ganglia * Dendrites * Highly branched processes * Receive incoming information * Carry this information as an electrical signal to the cell body * Axon * Longer processes * Only one per neuron * Carry information to other cells * Larger diameter, faster conducting * Vertebrate axons are insulated with myelin sheaths * Myelinated (fast conducting) * Non-myelinated (slow conducting) * Synaptic terminal * Specialized ending of axon * Relays message to target cell by releasing neurotransmitters * Neurotransmitters are chemical first messengers

Nervous System * Figure 48.3, 48.4 (structure of the neuron), * Sensory input—Integration—Motor output * Involves the rapid transfer of information through the body by electrical signals or nerve impulses. * Sensory inputs are integrated and lead to motor outputs

Neurotransmitters * Chemical first-messengers
Synapses
* Contact between synaptic, terminal, and target cell

Support Cells * Glia * From the Greek word glue * Radial Glia: Form tracts for neuron growth in the developing embryo. * Astrocytes * Structural and metabolic support in the Central Nervous System—CNS (brain and spinal cord) * Form tight junctions resulting in the blood-brain barrier. * Oligodendrocytes * In CNS * Form myelin sheath that insulates the axon of vertebrates

Schwann Cells * In PNS (peripheral nervous system) * Form myelin sheath that insulates the axon of vertebrates * Figure 48.13

Nodes of Ranvier * Noninsulated regions along the axon * Saltatory (means jumping) conduction of nerve impulses

WHAT IS THE DISTRIBUTION OF SODIUM IONS? Low [intracellular]

Difference in fluid composition inside and outside a cell * Plasma membrane separates two different environments * Internal environment is high in potassium, low in sodium. * External environment is low in potassium and high in sodium. * Internal environment inside the cell is slightly more negative * Figure 48.7

Leakage of ions through diffusion * Molecules tend to diffuse down their concentration gradient * Potassium tends to diffuse out of the cell * Sodium tends to diffuse into the cell * Countered by active transport * Sodium—Potassium ATPase (Sodium/Potassium Pump)

Membrane Potential * Difference in charge between inside of cell and environment * All cells have a membrane potential, but not all cells are excitable. * Excitable cells have gated ion channels (ion channel can be opened and closed) * Excitation—depolarization of the nerve membrane * Interior of the cell becomes less negative. * Hyperpolarization is when the cell becomes more negative * Depolarization—figure 48.8
Resting State: * Step 1 * -70 mV * Sodium and potassium voltage-gated ion channels are closed at the resting state * Voltage-gated * Opening-closing depends on membrane potential

Threshold stimulus * Step 2 * Smallest (depolarizing) voltage required to elicit an action potential.

Depolarizing Phase and Action Potential * Sodium channels open, influx of sodium * Potassium channels stay closed

Action Potential * Step 3 * Only triggered in the axon * This is the nerve impulse * Stereotypical * All action potentials look alike * All-or-nothing response * Rising Phase of the Action Potential * Sodium channels open * Potassium channels close

Falling phase of the Action Potential * Potassium channels are open * Sodium channels are closed * Membrane potential is now falling

In depolarization, the cell interior becomes—less negative.
How do you depolarize a cell? Open sodium channels

Refractory period * Hyperpolarization of the nerve membrane * Inside of cell is much more negative than the resting state * Interior becomes more negative than the resting state * Cannot generate another nerve impulse during this period

Undershoot phase * AKA refractory period (cannot generate another nerve impulse) * An example of Hyperpolarization * Sodium channel closed * Potassium channel still open, potassium still leaving the cell * Potassium gate closes more slowly than the sodium channel * Important in setting the directionality of the nerve impulse

Cells insulating the axons of vertebrates in the PNS—Schwann cells
_______ Has a high extracellular concentration and a low intracellular concentration. Sodium
A sodium potassium pump counters the leakage of ions across the plasma membrane. True
Na-K ATPase is an example of—Active transport
Hyperpolarize—interior of cell becomes—more negative
How do you hyperpolarize a cell? Open potassium channels
All cells have a membrane potential. True
Excitable cells have ____ion channels. Gated
In the depolarizing phase of an action potential, which channels are open? Sodium
In the rising phase of an action potential, which channels are open? Sodium
In the falling phase of an action potential, which channels are open? Potassium
In the resting phase, which channels are open? Not potassium or sodium
Hyperpolarization: interior of the cell becomes—more negative.
Hyperpolarization, sodium channels are___ and potassium channels are _____—closed, open
Depolarization: interior of cell becomes less negative
Depolarization, sodium channels are _______ and potassium channels are _______ —open, closed
Myelin sheaths are formed by—oligodendrocytes and Schwann cells
Which hormone exerts antagonistic action to calcitonin? PTH
What happens when beta cells of the pancreas release insulin into the blood? Body cells take up more glucose
Which of the following trigger a phosphorylation cascade that results in the breakdown of glycogen? Binding of epinephrine (adrenaline) to a GPCR in liver cells
Amplification of a chemical signal occurs when: a receptor in the plasma membrane activates several g-protein…
The operation of the sodium-potassium pump moves: sodium ions out of the cell and potassium ions into the cell
Action potentials move along axons more slowly in: axons of small than in large diameter
Which of these represents the activated form of a G-protein? Alpha-GTP+beta(gamma)
The refractory, undershoot phase, of an action potential results because the ____ gate closes more slowly than in the ______ gate. Potassium, sodium
An action potential flowing away from the cell body towards another neuron would be traveling along the axon.
______ Pressure acts like _____ temperature causing biological membranes to “freeze.” High, low

Graded Potentials * Hyperpolarization * Increased negative membrane potential * More negative than the -70mV resting potential * Open potassium channel, potassium flows out, leaving a more negative internal environment. * Depolarization * Decreased membrane potential (less negative internal charge) * Open sodium channel, sodium flows in, more positive ions in the axoplasm

Action Potential * When depolarization reaches the threshold potential (e.g., -50 to -55 mV) * Trigger action potential by opening sodium channels * All-or-nothing response * Amplitude of the height of the peak is independent of magnitude of the depolarizing stimulus * Figure 48.11 (be able to tell which channels are open and closed and which are moving)

Propagation * Unidirectional * Due to refractory phase * Cm/s to 100—150 m/s * Depends on diameter of axon * Depends on insulation

Saltatory Conduction * Nerve impulses “jump” down axon * Myelin sheath insulates * Nodes of Ranvier * Electrical charges “jump” to these exposed (un-insulated) areas * Voltage-gated ion channels at the nodes * Depolarization diffused further with the insulation * More compact structure—saves space

Myelin Sheaths * High proportion of lipid that serves as insulation * Decreases electrical resistance. * Invertebrate neurons lack myelin * Fast conducting neurons have larger diameters * In order to decrease electrical resistance
**Know figure 48.11-5 in book for final exam**

Demyelinating Diseases: * Demyelinating diseases of the central nervous system include: * Multiple sclerosis (together with the similar disease called idiopathic inflammatory demyelinating diseases) * Vitamin B12 deficiency * Demyelinating diseases of the peripheral nervous system include: * Guillain-Barre syndrome and its chronic counterpart, chronic inflammatory demyelinating diseases *

What happens when the action potential reaches the synapse? * At the presynaptic membrane the action potential causes an influx of calcium. * Open voltage-gated calcium channels * Triggers fusion of synaptic vesicles in the presynaptic cell * Vesicles release neurotransmitters from the presynaptic membrane * Neurotransmitters (first messengers) will bind to specific receptors

The Synapse * Presynaptic membrane (before the synapse) * Unidirectional—nerve impulse goes in one direction * Postsynaptic membrane (after the synapse)—membrane of the target cell

Synapses: * Electrical—cells are in physical contact with each other * Gap junctions * Ion channels * Chemical * Most common * Neurotransmitters (chemical messengers) * Figure 48.15 * At a chemical synapse, the action potential results in influx of calcium through voltage-gated channels * This triggers fusion of synaptic vesicles * The vesicles release neurotransmitter from the postsynaptic membrane

Neurotransmitter * Binds to and alters the activity of ligand-gated ion channels on the postsynaptic membrane * Depending on the neurotransmitter and receptor, the postsynaptic cell may be excited or inhibited * Depolarized (excited cell) and hyperpolarized (inhibited cell) * If the neurotransmitter opens a Na+ channel on the postsynaptic membrane, the cell becomes: Depolarized * If the neurotransmitter opens a K+ channel on the postsynaptic membrane, that cell becomes: Hyperpolarized * A ligand is a small molecule that binds to a protein. True

Ligand * Small molecule that can bind to a protein * The substrate for an enzyme * An allosteric modulator * A hormone * A neurotransmitter
Ligand-gated
* The opening of a ligand-gated channel requires the binding of a small molecule.

To terminate the synaptic message: * The neurotransmitter is either broken down by an enzyme (such as acetylcholinestrerase) * Or taken back up by the neuron

Integration of multiple inputs * Nerve cell will receive inputs from other nerve cells * Both excitatory or inhibitory inputs

EPSP * Excitatory postsynaptic potential * Sodium channels are open * Depolarizing

IPSP * Inhibitory postsynaptic potential * Hyperpolarizing * Potassium channels are open

Summation * Add together the IPSPs and EPSPs that are impinging on the cell * Add together impulses arriving at the same time (temporal summation) * Add together impulses arriving at the same place (spatial summation) * Sums exceeding the threshold result in an action potential * Sums less than threshold result in no action potential

Figure 49.19**

Long-term Potentiation * Altering the strength of synaptic transmission * NMDA and AMPA glutamate receptors * Figure 49.20

Biogenic Amines * Norepinephrine (noradrenaline * Alos a hormone produced by the adrenal medulla * Excitatiory or inhibitory

neuropep