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MCDB 126B > Final > Flashcards

Final Flashcards

0
Q

Location of PI(4)P

A

Golgi

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1
Q

Location of PI(4,5)P2

A

Plasma membrane

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2
Q

Location of PI(3)P

A

Endosomes

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3
Q

What do Phosphoinosotides do?

A

They can recruit selected signaling proteins to different regions of the cell and can serve a scaffolding function. They can also serve as identity tags for different regions of the membrane.

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4
Q

IP3 function

A

Binds to IP3 receptors on sarcoplasmic reticulum and allows for calcium release.

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5
Q

DAG function

A

Activates protein kinase C which is a serine and threonine kinase with different downstream effects than PKA due to different specificities.

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6
Q

Lithium

A

Inhibits inositol 1-phosphatase and downregulates the synthesis of PIs that are involved in second messenger signaling. It is nonspecific.

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7
Q

Pleckstrin homologous domains

A

Domains found in a variety of proteins that bind to phosphotidyl inositides (PIs). There are a lot of different conformations and types of pleckstrin homologous domains so they recognize different PIs. This is the way that proteins can recognize PIs and recruit PLC to the membrane where it can carry out it’s catalytic function.

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8
Q

PLC beta

A

Activated by Gq beta gamma subunits and alpha subunits.

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9
Q

PLC gamma

A

Activated through a pathway involving receptor tyrosine kinases. Once activated the receptor phosphorylates tyrosine residues on substrates which serves as a docking site for SH2 domains. These can then activate PLC gamma which will cleave PIP2 into IP3 and DAG..

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10
Q

What is the major calcium sensing protein in animal cells?

A

Calmodulin: capable of binding 4 different calciums in regions called EF hands. Binding induces a conformational change depending on how many are bound (2-4 to activate), which exposes it’s active sites that can either activate or inhibit proteins.

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11
Q

What are some sources of calcium

A

Extracellular: voltage gated calcium channels and various ligand gated channels.
Endoplasmic Reticulum: IP3 receptors and ryanodine receptors.

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12
Q

What are some calcium removal mechanisms?

A

Plasma membrane Na/Ca exchanger. Calcium ATPase pump. Mitochondria. Rapid removal and effective buffering.

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13
Q

What are some key features of calcium signaling

A

Amplification, spatial localization (allows for discrete transduction events within the cell), or propagation as a wave of oscillations due to complex positive and negative feedback of calcium on IP3 receptor (low concentration of calcium activates IP3, high concentration inhibits IP3).

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14
Q

Protein Kinase C

A

Phosphorylates hydroxyl group of serine and threonine residues within a consensus sequence. 3 subfamilies (~10 isozymes). Has regulatory and catalytic domains connected by a hinge region. Involved in: vascular smooth muscle contraction (alpha 1 adrenergic receptor), neurons in autonomic ganglia (M1 receptor), implicated in addiction (amphetamine, cocaine; dopamine uptake stimulated by PKC).

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15
Q

Phorbol esters

A

(TPA/PMA). Potent tumor promoters that mimic DAG and activate cPKC and nPKC. Are also potent inflammatory inducers. Longer lasting in the cell than DAG.

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16
Q

Classical PKC

A

cPKC:(Alpha, beta I, beta II, and gamma): require DAG, Calcium, and phospholipid for activation. DAG and calcium work synergistically.

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17
Q

Novel PKC

A

nPKC:(delta, epsilon, n, and theat): require DAG but not calcium.

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18
Q

Atypical PKC

A

(I, squiggly, N1): require neither calcium nor DAG.

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19
Q

What is the mechanism of activation of protein kinases?

A

Removal of autoinhibitory pseudosubstrate domains. Some protein kinases with this mech include PKA, CaMKII, and PKC.

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20
Q

CaMKII

A

Activated by calcium. Can then phosphorylate substrates.

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21
Q

How is PKC activated?

A

Activated by DAG, calcium, and PS which bind to regulatory domains causing a conformational change that exposes the active site of the catalytic domain.

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22
Q

Calcium ionophores

A

Used to artificially raise calcium concentrations. They are pores that allow calcium to flow. This bypasses the rest of the pathway.

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23
Q

Nitric Oxide

A

Synthesized from Arginine and oxygen via nitric oxide synthase. This is a calcium dependent synthesis. Also forms citrulline in the process. Can diffuse from endothelial cells to cause relaxation of smooth muscle cells by activating guanylyl cyclase which increases levels of cGMP, which in turn activates protein kinase G. PKG can then activate MLC Phosphatase which can dephosphorylate and inhibit myosin light chain leading to relaxation. Also decreases calcium levels via PKG.

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24
Q

Guanylyl cyclase

A

Contains a heme group. Catalyzed cGMP formation from GTP. Nitric oxide binds to the heme group to activate guanylyl cyclase.

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25
Q

Nitric Oxide Synthase

A

Activated by Calcium-Calmodulin. Catalyzes synthesis of nitric oxide from Arginine. Synthetic Arginine analogs (NMME and L-NAME) inhibit nitric oxide synthase.

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26
Q

Organic nitrovasodilators (nitroglycerine) and NO donors (nitroprusside)

A

Work to create their own NO and get coronary arteries dilated.

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27
Q

cGMP phosphodiesterase inhibitors

A

Inhibit cGMP PDE which leads to increased cGMP levels giving higher activity of PKG leading to relaxation.

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28
Q

cGMP PDE V inhibitors

A

Sildenafil/ Viagra, Levitra, Cialis: used in the treatment of erectile dysfunction.

29
Q

Development of the pituitary

A

The posterior pituitary is nervous tissue derived from an outpouching of the brain. The anterior is derived from an outpouching of the bucal cavity (rathkes pouch) and is ectodermal tissue.

30
Q

Anterior pituitary hormone release

A

Releasing hormone is real eased from the hypothalamus and travels part way down the infundibulary stalk. The neuroendocrine cells release the releasing hormone into a portal system blood supply that is localized to the anterior pituitary. Once the multiple different types of cells encounter the releasing hormone they release the anterior pituitary hormones into the blood supply to go to target tissues. Frequently these target tissues release ultimate hormones upon interaction with the anterior hormones. This 3rd set of hormones can then go into the blood supply to the final target tissue.

31
Q

Posterior pituitary hormone release

A

Much more simple than anterior hormone release. The hormones are made in neuroendocrine cells of the hypothalamus and travel down these cells down the stalk until they reach the posterior pituitary where there is a blood supply. The hormones (oxytocin and vasopressin can fit through small fenestrations in the capillaries allowing them to enter the blood supply and be carried to target tissues.

32
Q

Drugs used to stimulate uterine smooth muscle contractions

A

Oxytocin: (pitocin is the same molecule just synthetically derived).
Ergometrine: rarely used anymore. Fungal. Was a cause of spontaneous abortions.

33
Q

Drugs used to inhibit uterine smooth muscle contraction

A

Oxytocin receptor antagonists (atosiban): given for maybe a couple of days to prevent labour; it can have side effects so they just give it long enough until they can stimulate lung maturation with glucocorticoids.

Beta 2 receptor agonists (salbutamol: short acting agonist used for asthma): inhibit contraction by stimulating Gs which leads to phosphorylation and inactivation of MLCK.

Dihydropuridine calcium channel blocker.

34
Q

Roles of oxytocin

A

Acts on smooth muscle via Gq stimulation to cause contraction. Involved in the milk letdown “reflex”. Also involved in uterine smooth muscle contraction during and after childbirth. Typically given after childbirth to prevent excess bleeding during expulsion of the placenta.

35
Q

What are some roles of oxytocin

A

Milk letdown reflex, uterine smooth muscle contraction, social interactions and bonding, pair bonding/ mother-infant bonding/ maternal behavior, increased empathy, increased trust, altruistic behavior within a group, generosity, defensive aggression to members outside of the group, decreased fear response, opposes weight gain and decreases food consumption.

36
Q

Vasopressin

A

Acts through V2 receptors in the collecting duct to increase cAMP and promotes insertion of aquaporins into the apical membrane causing water reabsorption. Oxytocin and vasopressin are 9aa proteins with disulfide bonds between aas 1 and 6.

37
Q

Pre-pro-hormones

A

Vasopressin and oxytocin fall into this class. Pre means that they are hormones destined for secretion. They have a 23 aa peptide at their amino terminus which is a signaling peptide that allows for the hormone to be recognized by a signal recognition particle and allow it to enter the rough ER where it is packaged into vessicles and transported across the plasma membrane. The signal peptide is cleaved off as it enters the ER. Once in the vesicle it is further processed by proteolytic cleavage (pro).

38
Q

Where are oxytocin and vasopressin synthesized and released?

A

Synthesized in the cell bodies (paraventricular and supraoptic nuclei) in the hypothalamus, and transported to release site in posterior pituitary.

39
Q

Targets of the anterior pituitary hormones

A

Thyroid, adrenal, stomach, pancreas, duodenum, ovary, testis.

40
Q

What types of cells are in the anterior pituitary

A

Lactotrophs (mammotrophs), somatotrophs, thyrotrophs, corticotrophs, gonadotrophs, melanotrophs.

41
Q

Lactotrophs

A

Prolactin releasing factors (oxytocin and TRH) and release inhibiting hormones (dopamine) are released from the hypothalamus. Prolactin (PL) is released from the anterior pituitary and is involved in the production of milk targeting the breasts. Final effect is to interact with the breasts to increase milk production and lactation. In males they are involved in increasing testosterone.

42
Q

Somatotrophs

A

Growth hormone releasing hormone (GHRH) is the excitatory stimulus released from the hypothalamus. Somatostatin is the inhibitory signal. The anterior pituitary releases growth hormone (GH aka somatotropin) which targets the liver. Final hormone is insulin-like growth factor (IGF1) called somatomedin. Growth hormone and IGF1 target bones and cause growth of long bones and increase in stature.

43
Q

Thyrotrophs

A

Hypothalamus releases TRH (thyroid releasing hormone). The anterior pituitary then releases TSH (thyroid stimulating hormone), which acts on the thyroid gland. Final hormones released are T3 and T4 which are important in increasing basalmetabolic rate. They control out body temperature and metabolism. In doing so they also increase oxygen and fuel utilization and are also important in development.

44
Q

Corticotrophs

A

Hypothalamus releases corticotrophic releasing hormone (CRH) which stimulates release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. Target is the adrenal cortex. Final hormone released is cortisol which is involved in increasing catabolic reactions and is a long term stress hormone. Also the source of endogenous glucocorticoids.

45
Q

Gonadotrophs

A

Hypothalamus releases gonadotropin releasing hormone. Anterior pituitary releases lutenizing hormone (LH) and follicle stimulating hormone (FSH) which target the gonads. Final effect is to stimulate ovulation, regulate testosterone, increase production of estrogen and gametes.

46
Q

Melanotrophs

A

Hypothalamus is tonically inhibited by dopamine. Anterior pituitary released melanocyte stimulating hormone (MSH) which dopamine causes the release of. Target is the skin and the final effect is increased skin pigmentation.

47
Q

What are nuclear receptors?

A

Intracellular receptors for small lipophilic ligands, which include various steroids and lipophilic vitamin metabolites.

48
Q

What are some hormones that act via nuclear receptors?

A

Derivatives of cholesterol (cortisol, aldosterone, estradiol, testosterone, and vitamin D3).

Derivatives of vitamin A (all trans retinoic acid, 9-cis retinoic acid)

Amino acid derivative (triiodothyronine (T3))

Metabolic intermediates (fatty acids and bile acids)

49
Q

Feedback regulation of anterior pituitary hormones

A

The anterior pituitary hormone negatively regulates the release of releasing hormones (short feedback loop). Most of these work through GPCRs, so it’ll be fast and short. The final hormones negatively regulate the release of anterior pituitary hormones as well as hormones released from the hypothalamus. This feedback loop is both long in terms of pathway length and long in terms of duration as it typically involves nuclear receptors and receptor tyrosine kinases.

50
Q

Properties of hypothalamic releasing hormones

A

Most are small peptides or small proteins. They are secreted in pulses, often in a diurnal pattern. Modulate specific GPCR on specific anterior pituitary cells. They have a short half life.

51
Q

What is the purpose of having a pulsatile hormone secretion pattern by the anterior pituitary?

A

Allows for the control of hormones so that they can be used when the individual is ready and active.

52
Q

How is secretion of growth hormone controlled?

A

GHRF stimulates secretion of anterior pituitary growth hormone, while somatostatin inhibits. Growth hormone negatively regulates release of GHRF from the hypothalamus. Growth hormone acts on the liver to stimulate release of IGF-1, which negatively regulates release of growth hormone and positively regulates release of somatostatin. Both IGF-1 and growth hormone act on peripheral tissue to cause growth.

53
Q

How does growth hormone and IGF-1 cause growth of peripheral tissue?

A

Released from somatotrophs of anterior pituitary. Causes decreased insulin sensitivity, increased lipolysis, increase IGF-1. Both IGF-1 and growth hormone cause increased protein synthesis and increased epiphyseal bone growth for bones whose growth plates have not yet fused. Stimulated by GHRH and sleep. Inhibited by somatostatin, and IGF-1 (negative feedback).

54
Q

What are some conditions involving excess growth hormone? How are they caused? Treated?

A

Gigantism: GH excess occurs early in life (rare). Acromegaly: (excess soft tissue growth) if GH excess occurs after the body stops growing. The latter won’t cause an increase in stature because the bone plates have fused. These are often due to a pituitary tumor of somatotroph cells and can be treated with tumor removal, somatostatin analog octreotide, dopamine agonist against bromocriptine, GH antagonist pegvisomant.

55
Q

Growth hormone receptor

A

Growth hormone binds to the dimerized receptor (receptor tyrosine kinase) resulting in conformational change and activation of the downstream signal transduction pathway via tyrosine phosphorylation.

56
Q

Pegvisomant MOA

A

Modified analog of growth hormone that acts as a receptor antagonist. Binding site 1 contains an amino acid substitution that improves binding to the receptor, while binding site 2 contains a single amino acid substitution that blocks the conformational change of the growth hormone receptor and thereby inhibits signal transduction.

57
Q

Growth hormone deficiency: hypothalamic and pituitary lesions (tumor,infection, congenital and genetic causes) leading to primary GH deficiency.

A

Dwarfism: if occurs early in life (10% due to hormonal causes; rest from other causes). Dwarfism due to GH deficiency results in short stature, with proportional limbs and trunk.
Adult hypopituitarism: weakness, fine wrinkling and pale skin, loss of sex drive, genital atrophy, menstraul cycle cessation.

58
Q

What are some reasons for decreased growth besides dwarfism and adult hypopituitarism. (Growth hormone is normal)

A

GH receptor defect in target tissues (laron syndrome).
IGF-1 deficiency.

Treatment: GH (somatotropin) and IGF-1 (mescasermin) replacement.

59
Q

Sermorelin

A

Analog of growth hormone releasing hormone which is used diagnostically if one wants to test for growth hormone secretion to check if the anterior pituitary cells are responsive. Acts on the anterior pituitary to cause release of growth hormone.

60
Q

Somatropin

A

Can act as growth hormone

61
Q

Somatostatin

A

Inhibits the release of growth hormone. Also inhibits the release of TSH and inhibits insulin and glucagon in the pancreas.

62
Q

Octreotride

A

Essentially a long lasting somatostatin used to inhibit pituitary secretion of growth hormone.

63
Q

Recombinant IGF-1 (Mescasermin)

A

Causes growth of peripheral tissue and can bypass growth hormone receptor deficiency of the liver.

64
Q

Bromocriptine

A

Dopamine antagonist that inhibits release of growth hormone from the pituitary.

65
Q

What usually causes hormone excess and how can it be treated?

A

Often due to benign tumor in pituitary or target tissue. Remove the tumor or can treat with an inhibitor. Can use an analog of hypothalamic release inhibiting hormone (e.g. Somatostatin, dopamine). Or an inhibitor of the synthetic pathway for the final hormone (inhibitor of thyroid synthesis or cortisol excess). Or can use an inhibitor or modulator of receptor for the final hormone.

66
Q

How can one treat hormone deficiency?

A

Hypothalamic releasing hormones are used diagnostically but not therapeutically. Replacement of anterior pituitary hormone (growth hormone). Or replacement of final hormone (e.g. IGF-1, cortisol, thyroid hormones).

67
Q

How is prolactin secretion controlled?

A

Prolactin doesn’t have another hormone that is released but instead acts on the mammary glands itself to increase milk production. Inhibited by dopamine and stimulated by PRF, TRH, suckling, and oxytocin. Prolactin causes feedback inhibition by causing an increase in dopamine release.

68
Q

Actions of prolactin

A

Promotes growth and function of mammary gland and milk production (oxytocin controls release). Increases maternal behavior. Decreases LH and FSH release and/or response of ovaries; decreased ovulation; basis for natural contraceptive while breast feeding.

69
Q

What are some causes for excess prolactin release?

A

Hyperprolactinemia: most common form of pituitary hyper function caused by microadenomas of lactotrophs.

Dopamine receptor blockers (side effect of some antipsychotic drugs is lactation).

70
Q

What is a treatment for excess prolactin?

A

Dopamine agonist (bromocriptine) suppresses prolactin secretion and shrinks prolactinomas. Used to decrease lactation and treat prolactin- secreting tumors.

71
Q

How can one increase milk production?

A

Use a dopamine antagonist

MCDB 126B (14 decks)

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