Chapter 23: Messengers and Receptors

Slower, widespread, longer, env, growth, development, homeostasis, endocrine, organs, cells, bloodstream

Chemical Signaling:

• Is ___ than electrical signaling but more ___ and ___ lasting effects

• Functions:

  • Response to the ___

  • ___ and ___

  • Maintaining ___

• Primarily through the ___ system with ___ and ___ that secrete chemicals to the ___

Autocrine, paracrine, endocrine, neural, neuroendocrine

5 Types of Chemical Signalling:

1. ___ signals that act on the same cell

2. ___ signals that act locally on nearby cells

3. ___ signals that are hormones that are carried by blood

4. ___ signals that are between neurons

5. ___ signals that are hormones secreted by neurons

Ligand-receptor binding, behavior, gene expression, signal reception, signal processing, signal response, signal deactivation

Signal Transduction:

• Is the ability of a cell to respond to ___-___ ___ by altering ___ or ___ ___

5 Steps:

1. ___ ___: messenger binds to its receptors in the plasma membrane or inside the cell

2. ___ ___: ligand-receptor

   interaction starts signaling process

3. ___ ___: final result is a change cellular function or gene expression

4. ___ ___: signal and transduction pathway is turned off

Dynamic, sensitivity, blocked, surface, intracellularly, cognate, occupied, affinity, dissociation constant, Kd, low, agonists, antagonists

Signal Reception:

Receptors:

• Are ___

• Can change ___

• Can be ___

• Found on cell ___ or ___

Receptor-Ligand Binding:

• Receptor for a specific ligand is a ___ receptor

• Receptor with bound ligand is ___

• Relationship of [ligand] and occupied receptor number is ___

• ___ ___ or ___ is the [free ligand] to occupy half of the receptors

• Receptors with high affinity have ___ Kd

• ___ are drugs that activate receptors

• ___ are drugs that prevent a change and prevent natural ligands from binding

Membrane, second, amplification, hydrophilic, intracellular, direct, hydrophobic

Signal Reception:

Receptor Location:

1. ___ receptors usually involve ___ messaging with signal ___

   • For ___ chemical signals

2. ___ receptors usually have a ___ signal response

   • For ___ chemical signals

GPCR, cyclic guanosine monophosphate, cGMP, diacylglycerol, DAG, inositol triphosphate, IP3, cyclic adenosine monophosphate, cAMP, calcium ions, Ca2+

Signal Processing:

2nd Messengers:

• All involved in ___ receptors

1. ___ ___ ___ (___) that opens ion channels and activates some protein kinases

2. ___ (___) that activates some protein kinases

3. ___ ___ (___) that opens Ca2+ channels and mobilizes stored Ca

4. ___ ___ ___ (___) that activates some protein kinases

5. ___ ___ (___) that binds to calmodulin and the complex then activates some proteins

Membrane, hydrophilic, 10^6, 1, multiple, different, same, different, different, change

Signal Processing:

Signal Amplification:

• Usually occurs with ___ receptors and ___ ligands

• 1 ligand can illicit a response from ___^___ (#) molecules

Integration:

• Cells must integrate all signals for the right response

• 3 Types of Integration:

  1. ___ (#) receptor activates ___ pathway(s)

  2. ___ receptors activate ___ pathway(s)

  3. ___ receptors activate ___ pathway(s) that can ___ the other

Mitogenesis, gene expression, apoptosis, migration, cell-cell interactions, sensory, metabolism, protein transport, secretion, contraction, protein synthesis, differentiation

Signal Response:

12 Examples:

1. ___

2. ___ ___

3. ___

4. ___

5. ___-___ ___

6. ___

7. ___

8. ___ ___

9. ___

10. ___

11. ___ ___

12. ___

Automatic, rapid, free ligand [], receptor sensitivity, number, down-regulation, signal [], receptor numbers, activity

Signal Deactivation:

• This mechanism is ___ and ___

• 2 Methods:

  1. Reducing ___ ___ ___

  2. Reducing ___ ___ or ___ (also called ___-___)

• This allows cells to stay sensitive to ___ ___ and ___ ___ and ___

Receptor-mediated endocytosis, desensitization

Signal Deactivation:

Down-Regulation:

• 2 Mechanisms:

  1. ___-___ ___ that reduce the receptor number

  2. ___ that alters receptors to lower affinity or prevent changes in cellular function

Ligand-gated ion channels, membrane, ionotropic, G protein-coupled receptors, GPCR, membrane, metabotropic, receptor kinase, membrane, metabotropic, nuclear, intracellular

4 Types of Receptors:

1. ___-___ ___ ___ that are ___ and ___ receptors

2. ___ ___-___ ___ (___) that are ___ and ___ receptors

3. ___ ___ that are ___ and ___ receptors

4. ___ receptors that are ___ receptors

Guanine-nucleotide binding protein, G protein, 7-membrane, 7-transmembrane alpha helices, alternating, loops, N, C, phosphorylation, cytosolic AA, G protein-coupled receptor kinases, GRK, protein kinase A, PKA

G Protein-Coupled Receptors (GPCR):

• Receptors change conformation when ligands bind which activates ___-___ ___ ___ or ___ ___

• G proteins are used by many ___-___ spanning receptors

• Receptors have ___-___ ___ ___ connected by ___ extracellular and cytosolic ___

• ___-terminus is exposed to ECF

• ___-terminus is exposed to cytosol

• Regulated by ___ of specific ___ ___

  • EX: ___ ___-___ ___ ___ (___) and ___ ___ ___ (___)

Guanine-nucleotide binding proteins, GTP, GDP, GEF, GAP, heterotrimeric, 40-45, alpha, beta, gamma, monomeric, 20-25, Ras, Rho, Rap, Rac

G Proteins:

• Also called ___-___ ___ ___

• Cycle between active state bound to ___ and inactive state bound to ___

• ___ exchange GDP for GTP

• ___ convert GTP to GDP

2 Types:

• Large ___ G proteins of ___-___ (#) KDa with ___, ___, ___ subunits

• Small ___ G proteins of ___-___ (#) KDa like ___, ___, ___, ___

Gs, as, adenylyl cyclase, cAMP, Gi, ai, adenylyl cyclase, cAMP, Gq, aq, phospholipase C, calcium, protein kinase C, PKC

Classes of Heterotrimeric G-Proteins:

1. ___ that has the ___ subunit and stimulates ___ ___ which increases ___

2. ___ that has the ___ subunit and inhibits ___ ___ which decreases ___

3. ___ that has the ___ subunit that mediates ___ ___ activation (which makes DAG and IP3), increases ___, and DAG activates ___ ___ ___ (___)

Resting, not, GDP, ligand, is, GTP, Ga, Gby, activate, inhibit, target proteins, transduction, GTP, GDP, inactivates, recombine, inactive G protein

Activity of Heterotrimeric G Proteins:

1. ___ state where GPCR isn’t bound to a ligand and G protein ___ bound, alpha subunit is bound to ___

2. ___ binds to GPCR and ___ bound to G protein, alpha subunit is bound to ___

3. ___ and ___ separate

4. Subunits ___ or ___ the ___ ___ and start signal ___

5. Subunit hydrolyses ___ to make ___ which ___ the subunit

6. Subunits ___ to make an ___ ___ ___

G-protein coupled receptor kinase, GRK, beta-arrestin, occupied, allosterically, GRK, phosphorylation, beta-arrestin, endocytosis

GPCR Regulation:

• Can be desensitized by ___-___ ___ ___ ___ (___) and ___-___

• ___ GPCR is ___ activated by ___ through a ___ rxn

• This recruits ___-___ to cause a rapid desensitization which leads to ___

Activates, adenylyl cyclase, ATP, cAMP, inactivates, adenylyl cyclase, protein kinase A, PKA, serine/threonine kinase, exchange-protein-directly-activated-by-cAMP, Epac

G Protein Regulation:

• When GTP-Gas binds, it ___ the enzyme ___ ___ that converts ___ to ___

• When GTP-Gai binds, it ___ the enzyme ___ ___

• Then cAMP activates ___ ___ ___ (___) (a ___/___ (AA) ___) and ___-___-___-___-___-___ (___)

Adenylyl cyclase, ATP, cAMP phosphodiesterase, 5’AMP, degrade glycogen, produce FA, HR, BP, reabsorb water, bone resorption

cAMP:

• Made by ___ ___ from ___

• Degraded by ___ ___ into ___

Functions:

1. Epinephrine stimulates muscles and liver to ___ ___

2. Epinephrine stimulates adipose to ___ ___

3. Epinephrine stimulates cardiovascular tissues to increase ___ and ___

4. Antidiuretic hormone stimulates the kidney to ___ ___

5. Parathyroid hormone stimulates bone tissue to cause ___ ___

2 regulatory, 2 catalytic, phosphorylate, ion channels, cytoplasmic targets, gene expression

cAMP Activates PKA:

• cAMP activates PKA by binding to the ___ (#) ___ subunits to dissociate from the ___ (#) ___ subunits which then can ___ target proteins

• PKA can regulate cellular functions by modulating ___ ___, ___ ___ like enzymes, and ___ ___

Phosphofructokinase 2/fructose bisphosphatase-2, fructose-2,6-bisphosphate, transcription factor cAMP response element-binding protein, CREB, cAMP response element, CRE, TGACGTCA

EX of cAMP Activating PKA:

• EX: target protein: ___ ___/___ ___-___ which then regulates ___-___,___-___ levels

• EX: gene expression: binds and activates ___ ___ ___ ___ ___-___ ___ (___) which binds to the gene ___ ___ ___ (___) with the code ___ (8)

G proteins, Gaq, phospholipase Cb, PLCB, phosphatidylinositol-4,5-bisphosphate, PIP2, inositol-1,4,5-triphosphate, diacylglycerol, Ca2+ channels, ER, protein kinase C, PKC, phosphorylates, ser, thr

IP₃ and DAG:

• Ultimately regulated by ___ ___ subunit ___ which stimulates the enzyme ___ ___ (___) which cleaves ___-___,___-___ (___) into ___-___,___,___-___ (IP₃) and ___ (DAG)

• IP₃ binds to and opens ___ ___ in the ___ for physiological effects

• DAG activates ___ ___ ___ (___) which then will ___ specific AA ___ and ___

Activate platelets, contract muscles, secrete insulin, secrete amylase, degrade glycogen, antibodies

Functions of IP₃ and DAG:

1. Thrombin stimulates blood platelets to ___ ___

2. Acetylcholine stimulates smooth muscle to ___ ___

3. Acetylcholine stimulates the pancreas (endocrine) to ___ ___

4. Acetylcholine stimulates the pancreas (exocrine) to ___ ___

5. Antidiuretic hormone stimulates the liver to ___ ___

6. Foreign antigens stimulate B lymphocytes to make ___

Epinephrine, a1-andrenergic, smooth muscles, blood vessels, contraction, inhibition, glycogen, GPCR, Gaq, phospholipase Cb, Ca2+, calmodulin, kinase, phosphorylate, glycogen synthase

Main IP₃ Pathway:

• ___ hormone binds to ___-___ receptors found on ___ ___ and ___ ___ for ___ and ___ of ___ synthesis

• The receptor is a type of ___ which activates the ___ subunit to then activate ___ ___

• Resulting IP₃ releases ___ which binds to ___ and activates a ___ to ___ and inactivate ___ ___

<0.1, Ca ATPases, plasma membrane, Ca ATPases, smooth ER membrane, Na+/Ca2+ exchangers, plasma membrane, mitochondria, IP3 receptors, smooth ER, ryanodine receptors, smooth ER, Ca induced-Ca release

Ca²⁺ Regulation:

Maintaining [] (red):

• [] in cytosol kept at ___ (#) uM

1. ___ ___ in the ___ ___ to keep Ca out

2. ___ ___ in the ___ ___ ___ to take cytosolic Ca to the lumen

3. ___/___ ___ in the ___ ___ keep cytosolic Ca out

4. ___ transport Ca in

Increase Cytosolic [Ca²⁺] (blue):

5. ___ ___ release Ca from ___ ___

6. ___ ___ release Ca from ___ ___ (is a ___ ___-___ ___ mechanism)

Calmodulin, calcineurin, phosphatase, synaptotagmin, egg, early embryonic, right-left axis patterning, organ, bone, blood clotting, brain, neurotransmission, heart, muscle

Ca²⁺ Effectors and Functions:

Effectors:

• ___

• ___ which is a ___

• ___ in neurons

Functions in Body:

1. ___ activation

2. ___ ___ events

3. ___-___ ___ ___

4. ___ development

5. ___ formation

6. ___ ___

7. ___ function and ___

8. ___ function

9. ___ function

Neurotransmitters, synaptic vesicles, t-SNARE, v-SNARE, synaptotagmin

Ca²⁺ and Neurons:

• Stimulates secretion of ___ from the ___ ___

• Docking and fusion is mediated by ___-___ and ___-___ proteins that are allowed to interact by ___ which is a Ca sensor in the vesicle

Ca binding protein, intracellular Ca receptor, 4, affinity binding sites, enzymatic

Calmodulin:

• Is an important ___ ___ ___ / ___ ___ ___

• Has ___ (#) high ___ ___ ___

• No ___ activity

• Activates other cellular molecules

Protein kinase-associated receptors, receptor, protein kinase, tyrosine, serine/threonine, growth factor, insulin, IGF-1, cycle, migration, metabolism, proliferation

Receptor Kinase:

• Also called ___ ___-___ ___

• Work as a ___ and ___ ___

2 Types:

• ___ kinase

• ___/___ kinase

Subtypes:

• ___ ___ receptors

• ___ receptors

• ___-___ receptors

Functions:

• Mediate cell ___, ___, ___, and ___

Epidermal, EGF, transforming, alpha, TGFa, platelet-derived, PDGF, transforming, beta, TGFb, fibroblast, FGF, interleukin-2, IL-2, colony-stimulating factor-1, CSF-1, Wnts, hedgehogs, neuronal, NGF

Growth Factor (GF) Families That Bind to Receptor Kinases:

1. Tyr kinase receptors on epithelial and mesenchymal cells with ___ GF (___)

2. Tyr kinase receptors on epithelial and mesenchymal cells with ___ GF ___ (___)

3. Tyr kinase receptors on mesenchyme, smooth muscle, and trophoblast cells with ___-___ GF (___)

4. Ser/thr kinase receptors on fibroblastic cells with ___ GF ___ (___)

5. Tyr kinase receptors on mesenchyme, fibroblast, etc cells with ___ GF (___)

6. 3 subunit complex receptors on cytotoxic T lymphocytes with ___-___ (___)

7. Tyr kinase receptors on macrophage precursors with ___-___ ___-___ (___)

8. Frizzled (7-pass protein) receptors on embryonic cells with ___

9. Patched (7-pass protein) receptors on embryonic cells and melanocytes with ___

10. Also ___ GF (___)

1 polypeptide chain, transmembrane, domains, extracellular, domain, cytosolic, tyr kinase, dimerization, 2, autophosphorylation

Receptor Tyr Kinase: Structure and Activation:

Structure:

• Is a ___ ___ ___ with a ___ segment

• Have distinct ___

  • The ___ portion has the ligand-binding ___

  • The ___ portion has the ___ (AA) ___

Activation:

• ___ of ___ (#) tyr kinase(s) join when a ligand binds

• They undergo ___ from each other

Cascades, autophosphorylation, cytosolic proteins, phosphotyrosine, SH2 domain, Ras signaling, PI3-kinase, phospholipase Cy signaling

Receptor Tyr Kinase: Signal Transduction:

• Start ___

• ___ step causes recruitment of specific ___ ___ that must have a sequence of AA that recognize ___ residue

  • Sequence of AA called ___ ___

• Those proteins can activate different signal transduction pathways at the same time

  • EX of pathways: ___ ___, ___-___, ___ ___ ___

Monomeric G, GRB2, Sos, GEF, GDP, GTP, phosphorylation, transcription factors, gene expression, GTP, GAP

Receptor Tyr Kinase: Ras Signaling Pathway:

• Ras is a ___ ___ protein

• The protein bound to the phosphorylated tyr has a ___ (SH2 domain) and ___ (a ___ of Ras) that replaces ___ with ___

• GTP-Ras causes ___ rxns towards ___ ___ for ___ ___

• GTP-Ras is inactivated by hydrolysis of ___ by ___

GTP-Ras, Raf, p-Raf, mitogen activated protein kinase kinase, MEK, ser/thr, p-MEK, mitogen-activated protein kinases, MAPK, tyr/thr, MAPK, transcription factors, cell growth, division

Receptor Tyr Kinase: Ras Signaling Phosphorylation Rxns:

1. ___-___ phosphorylates ___

2. ___-___ phosphorylates ___ ___ ___ ___ ___ (___) at ___/___ residues

3. ___-___ phospohorylates ___-___ ___ ___ (___) at ___/___ residues

4. ___ phosphorylates ___ ___ for ___ ___ and ___

Alpha, beta, b, insulin receptor substrate I, IRS-1, Ras, GRB2, PI3-kinase

Receptor Tyr Kinase: Insulin Signaling:

• Receptor Tyr Kinase has 2 subunits: ___ and ___

• The ___ subunit phosphorylates ___ ___ ___ ___ (___-___) which is the SH2 domain which can then stimulate 2 pathways:

  1. ___ pathway by recruiting ___

  2. ___-___ pathway

Phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate, PIP2, phosphatidylinositol-3,4,5-trisphosphate, PIP3, protein kinase B, PKB, Akt, PTEN, phosphatase

Receptor Tyr Kinase: PI3-Kinase:

• ___ ___-___ (PI3-Kinase) will phosphorylate ___-___,___-___ (___) to become ___-___,___,___-___ (___)

• Then that will bind to ___ ___ ___ (___) or (___) that will then phosphorylate other kinases

• PIP3 is converted back to PIP2 by ___ which is a ___

Glucose uptake, GLUT4, vesicles, membrane, glycogen synthase, glycogen synthase kinase 3, GSK3

Receptor Tyr Kinase: Akt Function:

• Causes ___ ___ by moving ___ from ___ to ___

• Causes activation of ___ ___ by phosphorylation and reducing the activity of ___ ___ ___ ___ (___)

Endocrine, circulatory, [], specific receptors, intracellular, nuclear, gene expression, proteins, ion channels, polypeptides, AA, steroids

Hormones Basics and Types:

• Are chemical signals from the ___ system that are secreted into the ___ system

• Small ___

• Act on ___ ___

• Usually involved in ___ or ___ receptors

• Functions:

  • Changing ___ ___

  • Activate/inactivate ___ or ___ ___

• 3 Types:

  1. ___

  2. ___ derivatives

  3. ___

AA, peptides, proteins, steroids, AA, arachidonic acid

EX of Hormones:

1. ___

2. ___

3. ___

4. ___

5. ___

6. ___ ___

Steroid hormones, gene expression, steroid hormone, hormone binding, DNA binding, regulatory

Nuclear Receptors:

• Usually involve ___ ___ as ligands that usually regulate ___ ___

• Receptors are ___ ___ receptors

• 3 Domains:

  1. ___ ___ domain

  2. ___ ___ domain with high homology

  3. ___ domain

Monomers, heat shock proteins, HSP, dimerized, steroid-response elements, SRE, co-regulators, genomic ER, membrane-bound ER, GPER

Steroid Hormone Receptors:

• Cytoplasmic receptors are usually ___ that are bound to ___ ___ ___ (___) which then go to the nucleus

• Nucleus receptors become ___ when the hormone binds

• Then the receptors bind to ___-___ ___ (___) and interact with ___-___ to modulate gene expression

• Steroid Receptors can activate 3 Main Pathways:

  1. ___ ___ pathway

  2. ___-___ ___ pathway

  3. ___ pathway

Crosstalk, many, many, same

Integration of Different Signaling Pathways:

• Through ___

• Cells integrate different signals for the right response

• 1 receptor can activate ___ pathway(s) or ___ pathway(s) can converge to make the ___ molecule(s)

2

Overall, what is the point of chemical signal transduction?

1. to internalize proteins that can then be degraded in the lysosomes

2. to sense and respond to the environment outside the cell

3. to adjust a cell’s energy needs to the local environment

4. to detect when a cell needs to move, and then move

3

Why is the consequence of epinephrine so different for heart cells and liver cells?

1. The epinephrine receptors on the surface of their target cells are different.

2. The epinephrine receptors are more abundant on the surface of heart cells.

3. The proteins stimulated by the bound epinephrine receptor are different in heart cells and liver cells.

4. Different amounts of epinephrine reach each different type of target cell.

1, 4, 3, 2

Place the following steps of signal transduction in order

1. A messenger (ligand or signal) binds to its receptors

2. The signal and transduction pathway is turned off.

3. There is a change cellular function or gene expression

4. The ligand-receptor interaction initiates the signaling process.

1

Which is an example of a hormone in action?

1. A peptide made in the liver promotes uptake of AA from the blood throughout the body.

2. A steroid causes nearby cells to become pigmented.

3. A derivative of tryptophan causes a tissue, next to the one in which it is produced, to show signs of inflammation.

4. a and b

5. b and c

4

Which of the following mechanisms would you associate with an antagonist drug action?

1. a drug that binds postsynaptic receptors and mimics the effect of the endogenous neurotransmitter.

2. a drug that prevents the normal reuptake of neurotransmitters inside presynaptic terminals.

3. a drug that increases the enzymatic synthesis of neurotransmitters.

4. a drug that binds postsynapatic receptors and blocks the normal action of the endogenous neurotransmitter.

3

Which of the following hormones could have an intracellular receptor? (select all that apply)

1. Insulin (hydrophilic hormone)

2. Epinephrine

3. Cortisol

4. Angiotensin II (lipid-insoluble peptide hormone)

4

Which of the following is true regarding G-proteins

1. GAPS activate G-proteins exchanging GDP for GTP

2. GAPS activate G-proteins exchanging GTP for GDP

3. GEFs activate G-proteins exchanging GTP for GDP

4. GEFs activate G-proteins exchanging GDP for GTP

1

When luteinizing hormone binds to its receptor (LHR) on ovarian granulosa cells, there is an increase in the gene expression of 3β-hydroxysteroid dehydrogenase (HSD). This increases progesterone production from these cells. LHR is a G-protein coupled receptor that when activated, increases intracellular cAMP.

What type of G protein binds to the LHR?

1. Gαs

2. Gαi

3. Gαq

4. Ras

56?!

58?!

3

Consider a mutant liver cell isolated from a liver cancer patient. This cell contains about 104 molecules of active protein kinase A, even in the absence of epinephrine. What is a reasonable genetic explanation?

1. The cell’s phosphorylase kinase gene has a mutation that makes the kinase active all of the time.

2. The cell’s glycogen phosphorylase gene has a mutation that makes the phosphorylase active all of the time.

3. The cell’s adenylate cyclase gene has a mutation that makes the cyclase active all of the time.

4. The cell’s adenylate cyclase gene has a mutation that makes the cyclase inactive all of the time.

4

Which of the following proteins has SH2 domains?

1. guanylyl cyclase

2. inactive large heterotrimeric G protein

3. the EGF receptor, a tyrosine kinase receptor

4. PLCγ

3

Prostate cancer is the most commonly diagnosed malignancy in males and the second most deadly. One area of investigation for understanding the development and progression of this cancer involves fibroblast growth factor (FGF) signaling. What type of receptor does FGF binds to?

1. GPCR

2. Intracellular steroid receptor

3. Tyrosine Kinase Receptor

4. Ionotropic Receptor

4

Prostate cancer is the most commonly diagnosed malignancy in males and the second most deadly. One area of investigation for understanding the development and progression of this cancer involves fibroblast growth factor (FGF) signaling.

The FGF receptor is a tyrosine kinase receptor that activates the Ras signaling pathway. Which of the following is NOT important in this signaling pathway

1. Sos

2. Ras

3. MAPK

4. Ca 2+ second messenger

5. Transcription factors

3

Which of the following is true regarding the comparison between GPCRs and RTKs

1. GPCRs have cytosolic sites for phosphorylation kinases, RTKs have an extracellular component that acts as the tyrosine kinase

2. GPCRs have multiple (3-5) transmembrane segments, RTKs have 2 transmembrane segment

3. Ligand binding of GPCRs results in activation of G-proteins and exchange of GDP for GTP, Ligand binding of RTKs results in dimerization and autophosphorylation

2

Which of the following is important for phosphatidylinositol-4,5-bisphosphate (PIP2) phosphorylation

1. Inositol triphosphate (IP3)

2. Phosphatidylinositol 3-kinase (PI 3-kinase)

3. Phosphatidylinositol-3,4,5-trisphosphate (PIP3)

4. Diacylglycerol

5. PLC

Add

Review?!