1
Q
Describe the transmembrane receptor involved in Receptor Tyrosine Kinase Signaling
A
- The extracellular portion has signal-binding site
- The portion embedded in the membrane is comprised of α-helices
- The intracellular portion is loaded with tyrosine molecules
2
Q
Describe the Receptor Tyrosine Kinase Signaling Pathway
A
- Growth factor (such as epidermal growth factor) binds each monomer causing them to come together as a dimer
- Once the dimer forms, they autophosphorylate
- The activated tyrosine kinase receptor then phosphorylates relay proteins
- Relay proteins move throughout the cell to elicit a cellular response
3
Q
Describe the energy input and output for receptor tyrosine-kinase activation
A
- The 6 activated tyrosine-kinase regions use 6 ATP to phosphorylate to become a fully activated receptor tyrosine-kinase
- This yields 6 ADP
4
Q
What are the 2 families of RTKs?
A
- ErbB
* Insulin-IGF
5
Q
Describe the ErbB Family of RTKs
A
*Receptor monomers must dimerize before autophosphorylation can happen
6
Q
Describe the IGF-1 Receptor of the Insulin-IGF RTK family
A
- Contains α and ß subunits which are bound together via disulfide bonds making it already a dimer
- The α subunit is the majority of the extracellular portion of the receptor and contains the ligand binding domain
- The ß subunit is some extracellular, but contains the membrane-bound α-helical portion as well as the cytoplasmic tyrosine kinase domain
7
Q
Describe how the Insulin-IGF RTK family pathway works
A
- When the hormone binds the extracellular segment of the receptor, it cross-phosphorylates from P1->P2->P3
- Once phosphorylation completes, it becomes an active tyrosine kinase and phosphorylates other proteins to elicit a cellular repsonse
- Autophosphorylation occurs immediately upon hormone binding
8
Q
Describe the Classical Testosterone Signaling Pathway
A
- T passes through the plasma membrane via diffusion
- T binds to receptor in cytoplasm activating it
- The hormone-receptor complex moves into the nucleus and binds to specific genes
- The bound protein stimulates transcription of the gene into mRNA
- The mRNA is edited and exits the nucleus to be used as a template for new proteins via translation
- The new proteins elicit a cellular response
9
Q
Describe Pathway 1 of the Classical Estradiol Signaling Pathway
A
- E2 diffuses through the plasma membrane and enters the cytoplasm to bind its receptors
- The E2 receptors dimerize to enter the nucleus
- The E2 receptors bind estrogen-response elements (ERE) in the nucleus or other gene promoters to increase the rate of gene expression
- This is a long term response of hours-days
10
Q
Describe the 2nd E2 Signaling Pathway
A
- E2 binds receptors presen on the plasma membrane
- The hormone-receptor complex stimulate activation of intermediary proteins
- Intermediary proteins signal other 2nd messengers w/in the cytoplasm resulting in enzyme phosphorylation or gene expression
- This can also affect RTKs and ion channels
- This is a short-term cellular response of minutes-hours
11
Q
Describe the 3rd E2 signaling pathway
A
- E2 diffuses into cytoplasm
- E2 directly acts to block molecules that induce cell stress
- This is an immediate effect within minutes
12
Q
Describe the 4th E2 signaling pathway
A
- Other agents such as GFs or dopamine bind their own receptors
- Protein kinase cascades occur resulting in phosphorylation of ER (estrogen receptors)
- The activate ERs dimerize and bind DNA promoters
- This affects gene expression
13
Q
Name the hormone
- Source: ovary, placenta, or emrbyo
- Function: promotes exual behavior, stimulates secondary sex characteristics, growth of reproductive tract, uterine contractions, and mammary gland duct growth, controls gonadotropin release, stimulates calcium uptake in bones, has anabolic effects
- Class: steroid
A
Estrogens (E)
14
Q
Name the hormone
- Source: ovary, placenta
- Function: acts synergistically with estrogen in promoting estrous behavior and preparing reproductive tract for implantation
- Class: steroid
A
Progesterone (P)
15
Q
Name the hormone
- Source: Posterior pituitary
- Function: stimulates uterine contractions, parturition, sperm and egg transport, facilitates milk ejection, possible leutolytic function
- Class: neuropeptide
A
Oxytocin (OT)
16
Q
Name the hormone
- Source: ovary, testis
- Function: inhibit and stimulate FSH
- Class: Glycoprotein
A
Inhibin-activin
17
Q
Name the hormone
- Source: Anterior pituitary
- Function: Regulating metabolism, provides background for supportive reproductive function
- Class: Glycoprotein
A
Thyroid Stimulating Hormone (TSH)
18
Q
Name the hormone
- Source: Anterior pituitary
- Function: Regulation of metabolism and parturition
- Class: Glycoprotein
A
Adrenocorticotropic hormone (ACTH)
19
Q
Name the hormone
- Source: Anterior pituitary
- Function: Regulation of metabolism
- Class: Protein
A
Growth Hormone (GH)
20
Q
Name the hormone
- Source: Anterior pituitary
- Function: Promotes lactation, stimulates corpus luteum function and progesterone secretion in some species, promotes maternal behavior, promotes tissue and bone growth
- Class: protein
A
Prolactin (PRL)
21
Q
Name the hormone
- Source: Anterior pituitary
- Function: Stimulates ovulation, corpus luteum function: stimulates secretion of progesterone, estrogen and androgen
- Class: Glycoprotein
A
Leutenizing Hormone (LH)
22
Q
Name the hormone
- Source: Anterior pituitary
- Function: Stimulates follicular growth, spermatogenesis, estrogen secretion
- Class: Glycoprotein
A
Follicle Stimulating Hormone (FSH)
23
Q
Name the hormone
- Source: Hypothalamus
- Function: stimulates the release of ACTH
- Class: Neruopeptide
A
Corticotropin releasing hormone (CRH)
24
Q
Name the hormone
- Source: Hypothalamus
- Function: Stimualtes release of thyroid-stimulating hormone and prolactin
- Class:Neruopeptide
A
Thyrotropin releasing hormone (TRH)
25
Name the hormone
* Source: Hypothalamus
* Function: inhibits release of growth hormone
* Class:Neuropeptide
Growth hormone inhibiting hormone (GHLH) a.k.a. Somatostatin
26
Name the hormone
* Source: Hypothalamus
* Function: Stimulates release of growth hormone
* Class :Neuropeptide
Growth hormone releasing hormone (GHRH)
27
Name the hormone
* Source: Hypothalamus
* Function: Stimulates release of FSH and LH from anterior pituitary
* Class: Neuropeptide
Gonadotropin Releasing Hormone (GnRH) a.k.a. Leutinizing hormone releasing hormone (LH-RH)
28
Name the hormone
* Source: Posterior pituitary
* Function: vasoconstrictor, helps retain water
* Class: peptide
Vasopressin a.k.a. Anti-Diruetic hormone (ADH)
29
Name the hormone
* Source: Hypothalamus
* Function: inhibits release of prolactin
* Class: Neuropeptide, biogenic amine
Prolactin inhibiting factor (PIF) a.k.a. Dopamine
30
Name the hormone
* Source: Testis
* Function: develops and maintains accessory sex glands, stimulates secondary sexual characteristics, sexual behavior, and spermatogenesis, has anabolic effects
* Class: steroid
Androgens
31
Name the hormone
* Source: Uterus
* Function: causes uterine contractions and is leutolytic
* Class: Prostaglandin
Prostaglandin F2α
32
Name the hormone
* Source: Ovary, uterus, embryonic membranes
* Function: uterine contractions, leutolytic, stimulates secretion of progesterone from CL
* Class: prostaglandin
Prostaglandin E2 (PGE2)
33
Name the hormone
* Source: Uterus
* Function: transfers iron from maternal system to developing embryo during gestation
* Class: glycoprotein
Uteroferrin
34
Name the hormone
* Source: placenta
* Function: LH activity, maintains corpus luteum of pregnancy in primates
* Class: Glycoprotein
Human chorionic gonadotropin (hCG)
35
Name the hormone
* Source: Placenta
* Function: dilates cervix and causes joint relaxation
* Class: protein
Relaxin
36
Name the hormone
* Source: embryo
* Function: maternal recognition of pregnancy in ruminants
* Class:interferon
Interferon tau
37
Name the growth factor
* Stimulates regrowth of epithelium following disruption of ovarian surface at ovulation
* Human myometrial cells respond to this factor by stimulation of their proliferation: their activites are additive when used in combination and synergistically enhanced by progesterone
* Class: Protein
Epidermal Growth Factor (EGF)
38
Name the growth factor
* Stimulates proliferation of various cell types required with blastocyst implantation and embryonic development
* Class: Protein
Fibroblast growth factor (FGF)
39
Name the growth factor
* Regulates steroidogenesis in granulosa cells in large ovarian follicles via aromatase activity
* Class: Protein
Insulin-like growth factor (IGF)
40
Name the growth factor
* Removal of fetus causes elevated levels of this growth factor but can be reversed by Androgens and Estrogen
* The fetus, via secretion of estrogen precursors, regulates placental and maternal production of this growth factor during pregnancy
Insulin-like growth factor-1 (IGF-1)
41
What hormone initiates granulosa cell's responsiveness to IGF-1 during follicular development
Estrogen
42
Describe the flow through the hypothlamus-Hypohyseal portal system using GnRH and LH as examples
* GnRH is secreted by hypothlamic nerve cells exiting at the axons
* GnRH enters the Median Eminence
* Hypohyseal portal vessels carry GnRH to the capillary plexus of the AP
* GnRH exits the vessels and binds to gonadotropes inducing LH secretion
* LH leaves the AP via cavernous sinus veins into general circulation
43
What is the hypophysis?
Both anterior and posterior pituitary
44
Where is the hypolthalamus located? What type of tissue is it comprised of?
* 3rd ventricle at the base of the brain
| * Neural tissue
45
What type of tissue is the anterior pituitary comprised of?
Secretory tissue
46
Where is the nerupophysis located? What type of tissue is it comprised of?
* directly connected to hypothalamus
| * comprised of neural tissue
47
Describe the location of the Magnacellular neruons including axon termination
* 2 main locations: paraventricular nuclei cells and supraoptic nuclei cell within the hypothalamus
* Axons extend down hypohyseal nerve tract and terminate within the neurpohysis
48
How is the neuropophysis vascularized?
carotid artery
49
Describe the flow of Oxytocin (OT) as a neruopophyseal hormone beginning with synthesis
* OT is synthesized in paraventricular cells
* 9 OT are produced with each neurophysin
* OT travels down hypophyseal nerve tract where it is cleaved from neurophysin
* OT enters neuropophysis and is stimulated to be released via veins into general circulation
50
Describe the neuro-endocrine reflex arc of OT initiated by a suckling calf
* Suckling sends a nerve imulse to the spinal cord and then the impulse reaches the brain
* Impulse causes supraoptic and paraventricular nuclei to secrete OT
* OT is released from neuropophysis, enters general circulation, and reaches the mammary gland
* OT binds to receptors on myoepithelial cells around alveoli
* Myoepithelial cells contract causing milk let down
51
How is the hypothalamus connected to the posterior and anterior pituitary?
posterior: directly
anterior: indirectly via hypohyseal portal plexus
52
Name the type of feedback mechanism
* Gonadal steroids are secreted by the gonads and enter the bloodstream
* They enter the hypothalamus to regulate GnRH secretion
* They can also directly affect the anterior pituitary and LH and FSH secretion
Long-loop feedback
53
Name the type of feedback mechanism
* Secretory products exit the AP and enter circulation
* Then they have a feedback effect on hypothalamus
* Ex: ACTH is secreted from anterior pituitary and enters general circulation to act as an endocrine hormone to feedback on CRH secretion on the hypothlamus
* Ex: TSH feedback on hypothalamus for TRH
Short-loop feedback
54
Name the type of feedback mechanism
* Dominant follicle secretes estradiol to have a paracrine feedback effect on adjacent secondary follicles
* Gonadal steroids, gonadal proteins (inhibin/activin), and growth factors use this mechanism as well
ultra-short loop feedback
55
What 2 hormones use the Adenylate cyclase-protein kinase A (PKA) system?
FSH and LH
56
Describe the general PKA system
* LH/FSH bind to its specific receptor that's coupled with adenylate cycles on the cell membrane
* Adenylate cyclase converts ATP to cAMP
* cAMP is 2nd messenger and interacts and activates PKA in the cytoplasm
* PKA has direct effects on enzymes in cytoplasm via phosphorylation and can influence gene transcription
57
How is the PKA system regulated
Phosphodiesterases (PDEs) take free cAMP and converti it to inactive 5' AMP
58
Describe activation of the PKA holoenzyme
* PKA has 2 catalytic subunits and 2 regulatory subunits
* Each regulatory subunit has 2 cAMP binding sites so it can bind a total of 4 cAMP
* Once cAMP binds, the catalytic subunits unbind and become active kinases
* These kinases then phosphorylate other proteins within the cytoplasm
59
Describe the general role of G-Proteins as intracellular couplers
* Hormone binds to G-protein coupled receptor on the plasma membrane
* Activated G-protein can transit within the membrane to interact with an enzyme to activate it and create a cellular response
* The hormone dissociates from its receptor so it becomes inactive
* G-proteins aren't destroyed in this process, but shuffle back and forth between inactivated receptors and enzymes
60
Describe G-protein cycling of activation and inactivation
* Inactive G-protein has GDP bound to the α-subunit and the ß and ¥ subunits are still together
* When hormone binds, GTP replaces GDP to activate the G-protein
* The GTP-α separate from the ߥ so it can stimulate a protein causing GTP to loose a phosphate and return to GDP
* The αߥ subunits return together in a resting state
61
Describe how G-proteins are activated by magnesium
* LH receptors are transmembrane receptors
* Carbohydrates on the extracellular component aid in hormone binding
* When LH binds, the tail of tis receptor incorporates Mg2+
* This causes activation of the G-protein
62
What are the 3 levels that cells can control the 2nd messenger PKA system?
* Level of hormone-receptor binding
* Level of G-proteins (inhibitory vs stimulatory)
* Level of cytoplasm (phosphodiesterases on cAMP)
63
Describe how the PKA system can affect gene expression
* Active catalytic subunits enter the nucleus and interacts with proteins to stimulate transcription/gene expression
* Catalytic subunits phosphorylate cAMP response element binding protein (CREB)
* CREB interacts with DNA inducing accumulation of transcription factors resulting in gene transcription and mRNA production
* This causes a cellular response
64
What hormone uses the 2nd messenger Ca2+-Calmodulin system?
LH for signal transduction
65
What type of binding does Ca2+-Calmodulin use?
Cooperative (allosteric)
66
Describe the general Ca2+-Calmodulin system
* 2 Ca2+ bind to Calmodulin (2 at the top and 2 at the bottome)
* The complex is then activated and has a conformational change
* The complex interacts with target proteins by wrapping around and phosphorylating the target protein
* This induces a cellular response
67
Describe the 2 modes of action for Ca2+-Calmodulin
* 1: Ca2+-Calmodulin complex is free in cytosol and interacts with the target protein (phosphodiesterase) to activate
* 2: Calmodulin is part of an inactive target protein (phosphorylase kinase) and interaction with the 4 Ca2+ ions causes activation of the target protein
68
What are the 5 major cellular targets Ca2+-Calmodulin can affect?
* Enzymes
* Receptors/ion exchanges
* Gap junctions
* Cell shape
* Metabolic effects
69
What are the 2 major enzymes Ca2+-Calmodulin can affect?
* G-protein subunits
| * Adenylate cyclase
70
What are the 2 major receptors/ion exchangers Ca2+-Calmodulin can affect
* EGF receptors
| * Na+/K+-Ca2+ exchanger
71
How does Ca2+-Calmodulin affect gap junctions?
Affects intracellular communication
72
How does Ca2+-Calmodulin affect cell shape?
The complex can bind cytoskeletal proteins
73
How does Ca2+-Calmodulin affect metabolic effects?
* Mitochondrial activity
* ER activity
* Gene transcription and other activities within the nucleus
74
What does PI stand for?
Phosphptidylinositol
75
What does PIP stand for?
Phosphotidylinositol-4-phosphate
76
What does PIP2 stand for?
Phosphotidylinositol-4,5-bisphosphate
77
What does IP3 stand for?
inositol-1,4,5-trisphosphate
78
What hormones use the phosphatidyinositol 2nd messenger pathway
LH, OT and PGF
79
What does DAG stand for?
Diacylglycerol
80
Describe pathway 1 of the phosphatidyl inositol 2nd messenger pathway which occurs in the cytoplasm
* Hormone binds to its receptor, activating phospholipase C
* Phospholipase C cleaves PIP2 into IP3 and DAG
* IP3 interacts with smooth ER which contains an IP3 sensitive Ca2+ channels to release Ca2+
* The release of Ca2+ activates calmodulin causing an increase of protein phosphorylation
81
Describe pathway 2 of the phosphatidylinositol 2nd messenger pathway that occurs in the membrane
* LH/PGF binds to its receptor and activates phospholipase C
* Phospholipase C cleaves PIP2 into IP3 and DAG
* DAG activates protein kinase C
* PKC then phosphorylates target protein
82
Describe activation of the Type 1 subtype of PKC
* Hormone binds, activating phospholipase C which cleaves PIP2 into IP3 and DAG
* IP3 interacts with IP3 sensitive Ca2+ channels, releasing Ca2+ into cytoplasm
* Ca2+ causes preliminary activation of PKC
* DAG interacts with Ca2+-activated PKC to complete activation
* Fully activated PKC can phosphorylate subsrates
83
Describe activation of type 2 subtype of PKC
* Hormone binds, activating phospholipase C which cleaves PIP2 into IP3 and DAG
* DAG interacts directly with PKC causing a Ca2+ membrane channel to open
* Ca2+ enters cytoplasm leading to a cellular response
* GTP-activated G-protein complex has a stimulatory αsubunit which activates Phospholipase C
84
Describe the 3rd pathway of the phosphatidyinositol 2nd messenger pathway
* OT binds its receptor, activating phospholipase C which cleaves PIP2 into IP3 and DAG
* DAG is the precursor for Arachondonic acid
* Arachodonic acid is a precursor for prostoglandins
* Results in formation of prostaglandins
85
Describe how the 3rd pathway of the phosphatidyl inositol 2nd messenger pathway is important for CL destruction
* In ruminants, increase of PGF2α is the main cause of CL destruction
* OT binds receptors within the uterine endometrium and proceeds with system
* PGF2α is released from the uterus and travels via counter-current exchange to ovary
86
Describe how the 3rd pathway of the phosphotidylinositol 2nd messenger pathway is important for parturition
* OT interacts with receptors within the uterine endometrium inducing phospholipase C activity and DAG generation
* DAG is metabolised into PGF2α which works on uterine endometrium and myometirum to stimulate contractions for parturition
ANS 452 Exam 1
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