endocrinology lecture 1 cell signaling

What is intracellular cell signaling

Signaling within a cell

Intercellular signaling

Signaling between cells

Autocrine signaling

Cell targets itself

Gap junction signaling

Cell targets another cell via gap junctions

Paracrine signaling

Cell targets nearby cell

Endocrine signaling

Cell targets distant cell through bloodstream

What synthesizes AND secretes hormones

Endocrine glands

How are hormones distributed through body

Move through blood and sent to every cell in body

Neurotransmitters

Secreted by neurons to target cells

Neurohormones

Hormones secreted by neurons rather than endocrine cell (ie dopamine)

Prostaglandins

Metabolize lipids and mediate inflammatory response

Is prostaglandin considered a hormone or other type of signaling molecule?

We’ve heard both (but I don’t know why so double check)

What does PGE2 do?

Prostaglandin that lowers blood pressure

What does PGF2a do?

Prostaglandin that increases blood pressure

Other types of signaling molecules

Exocrine regulator, pheromones

What’s an exocrine regulator

Signaling molec secreted into lumen or duct (of stomach?? Fact check)

Receptors

Molecules in a target cell that recognize signaling ligands

Membrane receptors

Located on cell membrane; bind to lipoPHOBIC signal molecules

Intracellular receptors

Receptors in cytoplasm or nucleus that bind to lipoPHILIC signal molecules

I think ligand binds in cytoplasm and then moved to nucleus?? Clarify

How are hormones classified

Source, mode of action, and biochemical classification

Which organs can source hormones?

Pituitary gland, pineal gland, thyroid gland, parathyroid gland, adrenal glands, hypothalamus, thymus, heart, kidney, GI tract, pancreatic islets

What « modes of action » can a hormone have?

Release of other hormones, maintenance of metabolic functions, stimulation of gonads, sexual promotion, maintenance of pregnancy, luteolysis

Types of biochemical classification

Peptide hormones (chains of a.a. including, peptides, polypeptides, glycoproteins), steroids (lipid derivatives from cholesterol), and amines (derived from tyrosine or tryptophan)

How are peptides synthesized?

Synthesized as prohormones and require further processing (like cleavage) to activate

How are peptides stored

Vesicles, undergo regulatory secretion (initiation of exocytosis of vesicles)

What is the solubility of peptides

Most are polar and water soluble, travel freely in blood

How do peptides interact with receptors

Bind receptors on cell membrane and transducer signal via use of secondary messenger systems

What are the effects of peptides

Fast onset transient changes in protein activity, gene expression changes can occur

Examples of peptides

Insulin, glucagon, prolactin, ACTH, gastrin parathyroid hormone

Effects of peptide

Fast onset transient changes in protein activity, gene expression changes can also occur

Synthesis of steroids

Synthesized in series of reactions from cholesterol

Steroid storage

Released immediately (constitutive secretion, whatever that means)

Solubility of steroids

Generally nonpolar due to hydrophobicity and require transport proteins to move through blood

Steroid receptors

Bind to intracellular receptors to change gene expression directly

Steroid effects

Alterations in gene expression, slower onset but longer duration than peptide hormones

Examples of steroid hormones

Cortisol, aldosterone, estrogen, progesterone, testosterone

Amino acid synthesis

Synthesized from amino acid tyrosine

Amino acid storage

Storage before release

Amino acid solubility

Some are polar, others are protein-bound

Amino acid receptors

Adrénaline acts on membrane receptors, while thyroid hormones act directly on nuclear receptors

Examples of amino acid derivatives

Adrénaline, thyroxin, triiodothyronine

Hypothalamic hormones (peptides)

Thyrotropin-releasing hormone (TRH, stimulates TSH release, shortest peptide 3 aa), gonadotropin releasing hormones (10 aa long, stimulate release of FSH and TSH)

Somatostatin

Growth hormone releasing hormone (40 aa or 44) stimulates release of growth hormone

Dopamine

Modified amino acid, inhibits release of prolactin

Corticotropin-releasing hormone (CRH)

(41 aa acid polypeptide, stimulates synthesis of pro-opiomelanocortin, POMC, and release of both beta-lipotropin (beta-LPH) and corticotropin (ACTH)

Glycoproteins hormones from anterior lobe of pituitary (also peptides)

Two carbohydrate moieties, two side by side polypeptide chains known as alpha subunit (same across all proteins) and beta subunit (different, distinguishes hormone function)

Hormone synthesis FOR PEPTIDE AND PROTEIN HORMONES

Hormone is synthesized and stored in secretory vesicles, goes from DNA —> mRNA in nucleus, ribosomes translate RNA to preprohormone, endoplasmic reticulum cleaves into prohormone, Golgi apparatus further turns into peptide hormone and stores in secretory vesicles

Levels of regulation for protein synthesis

Transcriptional level, translational level, post-translational level

Transcription al level of protein synthesis regulation

Modulators turn on or off gene promoter

Translational level

Modulators can stimulate translation, inhibit translation (like degrade RNA), modify translation (like splice pre-RNA to form different RNAs)

Post-translational level

Modify the protein

NOT A FLASHCARD BUT A REMINDER

Practice tracing peptide synthesis pathway on 02 signaling molecules slide 19

Conversion of pro insulin to insulin

(Proinsulin is precursor to insulin secreted by pancreas), enzymes clip off connecting peptide (C-peptide) to release active insulin, composed of two peptide chains A and B and connected by two disulfide bonds (S-S)

C-peptide only arises from…

Endogenous insulin (presence in blood indicates that at least some pancreatic insulin is being made)

What can be plasma c-peptide be used to measure in patients?

Measured in patients taking insulin to determine whether body is still capable of producing hormones, since pharmaceutical insulin does not contain c-peptide

What is the function of c-peptide?

Unknown

Organs that produce steroid hormones (usually end in -one)

Adrenal gland, gonads, placenta

Source of cholesterol for steroid synthesis

De novo (synthesized by cells) or from diet

De novo synthesis of cholesterol

Takes place in uncleared cells of mammals, particularly liver cells, from acetyl CoA

Diet-originated synthesis of cholesterol

Transport to tissues by low density lipoprotein (LDL), LDL binds to LDL receptors located in coated pits in surface of cells and the receptor, and then endocytosed into cell

Where is dietary cholesterol transported to for conversion to steroids?

Mitochondria

Tyrosine-derived amine hormones: catecholamines

Made by modifying side groups of tyrosine, examples include dopamine, norepinephrine, epinephrine

Tyrosine-derived amine hormones: thyroid hormones

Synthesized from two tyrosine’s and iodine atoms

key components of hormone receptors

Ligand-binding domain binds to specific hormone, effector domain responds to presence of the hormone bound to the ligand-binding domain and initiates biological response

Receptor agonist

Ligand that binds to receptor and gives a normal biological response (mimics normal ligand)

Receptor antagonist

Ligand that binds to a receptor but gives no response and blocks binding of other ligands

Three types of membrane receptors

Ligand-gated ion Channel, receptor tyrosine kinase, g-protein coupled receptors

Ligand-gated ion channels

Channel opens after binding without having to touch hydrophobic core, only open with binding

Receptor tyrosine kinases

Single membrane spanning membrane, monomeric of but dime rise upon ligand binding, and cytoplasmic domain contains tyrosine kinase activity which phosphorylates tyrosine residues when activated. EXCEPTIONS: insulin receptor and IGF-1 receptors already exist as dimers

Kinase

Enzyme that transfers phosphate groups from ATP to another protein

NOTE NOT FLASHCARD: explain binding process on slide 32

Slide 32

G-coupled protein receptors

Bind to n-terminal (extra cellular domain) and activate c-terminus (cytoplasmic domain, think c for cytoplasm)

G-Coupled Protein receptor

EXPLAIN BINDING PROCESS FROMSLIDE 32 and 33 and 34

What hormones interact with intracellular receptors

Steroid and thyroid hormones (ie estrogen, progesterone, testosterone)

QUESTION: are there both separate nuclear (intracellular) and cytoplasmic receptors? But both end up in nucleus eventually?

Question

How many domains are on nuclear receptors?

DNA binding domain (conserved), ligand binding region (less conserved), hinge region (short, nonconserved region), A/B domain

DNA binding domain

Part of nuclear receptor that is highly conserved (constant over evolution) where DNA binds

Ligand binding domain

Part of nuclear receptor that is less conserved than DNA binding domain and is where the ligand binds

Hinge region

Short non conserved region between dna binding and ligand binding parts of nuclear receptor, serves as hinge / separator between N and C terminus

A/B domain

Contributed to difference in size between receptor proteins; located at N-terminal

Elements necessary for the control of gene transcription

AF-1 in A/B domain, AF-2 in E/F domain

Examples of nuclear receptors

Thyroid hormones receptors (TR) and 1a,25(OH)2-vitaminD3; found in nucleus of target cells where they may be bound to co-repressor molecules that suppress DNA transcription

How do TR and 1a, 25 (OH)-2-viramin D3 bind to specific DNA sequences

form heterodimers with RXR - retinoid x receptor (type of nuclear receptor protein that binds to vitamin A derivatives that are also in the nucleus)

What two receptors are intracellular cytoplasmic

Cortisol and aldosterone receptors (GR and MR), are in cytoplasm before binding with ligand, and are bound to chaperone proteins (AKA heat shock proteins) that maintain an inactive state. After ligand binding they undergo nuclear translocation to bind to specific DNA sequences

Receptors for progesterone (PR), androgens (AR), and estrogens (ER) are found…

In nucleus before ligand binding or travel between two compartments; they also form homodimers