Carnegie 2

Mechanism of action of peptide/protein hormones and catecholamines

• cell surface receptors

• second messengers

• regulation of enzyme activity

• no latent period

Mechanism of action of steroid Hormones & Thyroid Hormones (Lipophilic)

• enter cells by diffusion

• intracellular receptors

• regulation of gene

• transcription

• latent period

Receptors (cell surface or intracellular)

• confer specificity

• can have different affinities

• can be saturated

• can be up-regulated or down-regulated to influence cell responsiveness (by the hormone itself or by another hormone)

• notion of permissiveness (sometimes accomplished by receptor up-regulation, but not always)

Example of permissiveness

Thyroid hormone is permissive of epinephrine-stimulated release of fatty acids by adipose tissue

What is hormone permissivness?

those that must be present for another hormone to exert its full effects, acting as a prerequisite or enhancer for a second hormone's action

MECHANISM OF ACTION OF HYDROPHILIC HORMONES

• Cyclic AMP (cAMP) second messenger system

• IP3 -Ca2+ & DAG second messenger pathways

Cyclic AMP 2 nd Messenger System

1. Binding of extra-cellular messenger to receptor activates a G protein, the or subunit of which shuttles to and activates adenylyl cyclase.

2. Adenylyl cyclase converts ATP to cAMP.

3. CAMP activates protein kinase A.

4. Protein kinase A phosphorylates inactive target protein, activating it.

5. Active target protein brings about desired response.

6. Cellular response

What is protein kinase?

An enzyme that phosphorylates and thereby induces a change in the shape and function of a particular intracellular protein

Possible things PKA can do

• Membrane effects

• Metabolic effects

• Gene expression

• Calcium fluxes

• Structural effects

Phosphodiesterase importance

• Necessary to deactivate cell so that it can be ready to be activated again

• Enzyme that catalyzes conversion of cAMP to AMP

IP3 -Ca2+ & DAG 2nd messenger pathways

1. Binding of extra-cellular messenger to receptor activates a G protein, the a subunit of which shuttles to and activates phospholipase C.

2. Phospholipase C converts PIP2 to IP3 and DAG.

3. IP3 mobilizes intracellular Cat

4. Ca2+ from ER activates calmodulin.

5. Cat-calmodulin complex activates Ca?+-calmodulin-dependent protein kinase (CaM kinase).

6. CaM kinase phosphorylates inactive target protein, activating it.

7. Activate target protein brings about desired response

8. Cellular response

1. Binding of extra-cellular messenger to receptor activates a G protein, the a subunit of which shuttles to and activates phospholipase C.

2. Phospholipase C converts PIP2 to IP3 and DAG.

3. DAG activates protein kinase C.

4. Protein kinase C phosphorylates inactive target protein, activating it.

5. Active target protein brings about desired response.

6. Cellular response

Second messenger pathways

different cells have different proteins/enzymes that can be modified by phosphorylation once a protein kinase is activated, allowing hormones to have varying effects depending on the specific cell being activated

the cAMP and Ca2+ pathways can ______ each other

• support

• calcium-activated calmodulin can influence adenylate cyclase activity

• protein kinase A phosphorylates calcium channels to open or close them

What do we mean when we say that hormones are POTENT?

• Don’t need a whole lot of each hormone for an appropriate response

• One hormone is amplified to create lots of products

Lipid-soluble hormones act within the nucleus- amplification

Amplification at step of synthesis of mRNA leading to increased physiology response

Thyroid hormone deiodination

• T4 enters cell (1º hormone released by thyroid gland)

• deiodination to T3 (T3 more easily reaches and binds in nucleur membrane)

• conveyed toward nucleus by binding protein – T3 easily traverses nuclear membrane

• nuclear receptor and activation of specific gene transcription

What is the ultimate goal of negative feedback?

Keep level of something within optimal range for the body

What is a physiological example of negative feedback?

Anterior pituitary → thyroid stimulating hormone → thyroid glands → thyroid hormone→ ANterior pituatary

1 hormone regulating a process negative feedback

acts to decrease its secretion once process or blood concentration of substance back in range

Process regulated in opposite directions by 2 different hormones

opposite effects on one factor (ex: blood glucose levels)

What is the ultimate goal of positive feedback?

reinforce successful actions and behaviors and to motivate continued growth and improved performance

Best example of positive feedback?

• Labour & delivery and hormonal control of breastfeeding

  • Brain stimulates pituitary gland to secrete oxytocin

  • Oxytocin carried in bloodstream to uterus

  • Oxytocin stimulates uterine contractions and pushes baby towards cervix

  • Head of baby pushes against cervix

  • Nerve impulses from cervix transmitted to brain

The endocrine function of the posterior pituitary gland

• composed of axonal terminals of neurons that originate in the supraoptic & paraventricular nuclei (SON & PVN)

• really a site of hormone storage

Both posterior pituitary hormones are _________ that are similar in structure

• nonapeptides

  • oxytocin

  • vaspressin

Oxytocin

uterine contractions & milk let-down (primarily PVN)

Vasopressin

also called antidiuretic hormone (ADH) – water conservation at the level of the kidney (primarily SON)

What are neurophysins I and II?

• components of oxytocin (I) & ADH (II) precursor molecules

• neurons of paraventricular and supraoptic neurons produce precursor molecules that consist of the hormone plus its neurophysin

• packaged into vesicles for transport to posterior pituitary

• endopeptidases cleave precursor – hormone stays with neurophysin carrier until hormone release by axonal terminals is stimulated (depolarization + Ca++ influx)

• neurophysins serve combined roles of structural component of hormone precursor molecules and carrier proteins during axonal transit

What is the neural stimulus of labour?

Baby’d head pushing against cervix

What is the endocrine response of labour?

Release of oxytocin

ADH has two effects that both act to increase blood pressure

• vasoconstriction of blood vessels

• water conservation by kidney

release of ADH results in ____ urine flow rate & production of a ______ urine

• low

• concentrated

What is the effect of alcohol on ADH secretion?

Suppress the release of ADH (cause feeling of dehydration)

What is diabetes insipidus?

• Autoimmune disease where you can’t regulate ADH production

• ADH needs to be taken to regulate this (easy to control with medication not like diabetes mellitus

Why is it called diabetes?

comes from ancient Greek, meaning "siphon" or "to pass through," referring to the excessive urination (passing of fluid) it causes, while the full name, Diabetes Mellitus, adds the Latin "mellitus" meaning "honey-sweet," because the urine of people with the condition was sweet due to excess sugar.

Describe the hypothalamic regulation of anterior pituitary hormone secretion

Stimulus → Hypothalamus (↑ Hormone 1 secretion) → 1 Plasma hormone 1 (in hypothalamo-pituitary portal vessels) → Anterior pituitary (↑ Hormone 2 secretion) → ↑ Plasma hormone 2 → Third endocrine gland († Hormone 3 secretion) → ↑ Plasma hormone 3 → Target cells of hormone 3 (Respond to hormone 3)

Hierarchic Chain of Command

The six classical anterior pituitary hormones

• LH and FSH

• TSH

• ACTH

• GH

• Prolactin

LH and FSH

gonadotropins involved in reproduction (egg & sperm development and stimulation of production of reproductive steroid hormones)

• GnRH (+) → FSH and LH → Germ cell development and gonads secrete hormones (F: Estradiol and progesterone, M: testosterone)

ACTH (adrenocorticotropic hormone)

CRH (+) → ACTH → adrenal cortex- linear 39 a.a. hormone that increases cortisol production

GH (growth hormone)

also called somatotropin (~200 a.a.)

• GHRH (+) and SS (-) → GH → liver and other cells → secrete IGF-1

• many organs and tissues- protein synthesis, carbohydrate and lipid metabolism

Prolactin

DA (-) → Prolactin → mammary gland development & milk production