Molecular Endocrine,1

MOLECULAR ENDOCRINEDEPARTEMENT OF PHYSIOLOGYSUMATERA UTARA UNIVERSITY2006

Definision of the Endocrine system The endocrine system is a collection of glands and organs that produce and regulate hormones in the bloodstream to control many functions of the body.

ENDOCRINE SYSTEMUses chemical signals for cell to cell communication

Coordinates the function of cells

Response to an endocrine signal occurs within minutes to hours

Glands A gland is a group of cells that produces and secretes, or gives off, chemicals. A gland selects and removes materials from the blood, processes them, and secretes the finished chemical product for use somewhere in the body. Some types of glands release their secretions in specific areas.

Hormones A hormone is a chemical produced in the body that interacts with a receptor in a target tissue to cause a change in the function of that tissue. There are various types of hormones in the body and include the exocrine (glands with ducts that release hormones for local action), and endocrine hormones.hormones carry messages from glands to cells to maintain chemical levels in the bloodstream that achieve homeostasis.

ENDOCRINE GLAND HORMON TARGET CELL PHYSIOLOGY RESPONSrelease

HYPOTHALAMUSTRHCRHGnRHGHRH/GHIHDAOXYADHTSHACTHFSH/LHGHPRLOXYADH++-++-ThyroidAdrenal CortexOvary/TestesAll TissuesBreastBreastKidney+++++++HIPOFISE ANTERIORHIPOFISE POST

Hormon as mediatorHormon as the same as neurotransmitter act as first messengerBinding with receptor of target cells and influence second messenger to give effect of the target cells, create physiological responsOnly hydrophilic hormon needs first messengerLipophilic hormon go directly into target cell and involve in DNA/RNA transcription form new protein

cell communication

Hormon ClassificationBased on its substance:Peptide and poly protein (TSH, Insulin, Parathyroid hormone)Amine (Thyroid hormone, epinephrine)Steroid (cortisol, aldosterone, testosterone)

Based on receptor location in target cells :HydrophilicLipophilic

HORMONE CLASSIFICATION(Based on the substance)

STEROIDNON STEROID:- AMINE- PROTEIN AND POLYPEPTIDE

Hormone ClassificationProteins-thyroid stimulating hormone, insulin, parathyroid hormone

Amino acids-thyroid hormone, epinephrine

Steroids-cortisol, aldosterone, testosterone

Based On their receptor locationHYDROPHILIC PEPTIDES AND CATHECOLAMINE Poorly soluble in lipid Cannot through lipid membrane barrier Binding with spesific receptor on the outer suface of plasma membraneLIPOPHILIC STEROID & THYROID HORMONE Easily pass through the surface membrane Binding with specific receptor inside the targe cell

Non-Steroid Hormones are secreted from both the thyroid and adrenal glands. Unlike steroid hormones, non-steroid hormones cannot directly cross the cell membrane. They regulate many functions including growth, hunger, thirst, and sex drive.

Steroid Hormones are derived from cholesterol and secreted from the adrenal glands, testis, and ovaries. They are Lipids which means that they can cross cell membranes easily. They stimulate cell growth and differentiation and regulate the synthesis of specific proteins.

Both steroid and non-steroid hormones enter the bloodstream after being secreted by the endocrine glands. They travel to other parts of the body where they locate specific cells called target cells.Target cells are cells that have receptors for specific hormones.Steroid hormones and non-steroid hormones have different ways of entering the target and both have separate types of target cells that they enter.

Hormone Receptors (cont)Receptors are classified by their locations1) Membrane receptors - Embedded in the cell membraneSpan the phospholipid bilayerHormone binds extracellularlyBinding alters receptor conformation, transmits intracellular signal (those famous G-proteins!)2) Cytosolic and nuclear receptors - in the cytoplasm or nucleus (genomic)Activated receptor binds to DNA and initiates/alters gene transcriptionHormone must enter cell first

ReceptorLigand binding specificityEffector specificity (signalling pathway)

Note-Different receptor with different effector specificity can bind the same ligand-Different receptor with different binding specificity may have the same effector specificity

AMINE HORMONEDerived from the amina acid tyrosine

Includes thyroid hormones and catecholamines

Stored until secreted

Receptor intra celluler and outer surface

Protein and Polypeptide Hormones: Synthesis and ReleaseFigure 7-3: Peptide hormone synthesis, packaging, and release

Protein and Polypeptide Hormone ReceptorsSurface receptorHormone bindsTransductionEnzyme activationOpen channelsSecond messenger systemsSynthesisFigure 7-5: Membrane receptors for peptide hormones

Steroid Hormones

Cytoplasmic or nuclear receptors (mostly)

Activate DNA for protein synthesis

Slower acting, longer half-life

Examples: cortisol, estrogen & testosterone

Steroid Hormones: ActionFigure 7-7: Steroid hormone action

What is a second messenger?An intracellular signalling molecule whse concentrarion increases (or decreases) in response to binding of an extracellular ligand to a cell surface receptor

Second messengers for hormone are : cAMP, cGMP, IP3, DAG, and Ca2+

Second messengersHormone stimulation of Gs protein-coupled receptors (GPCRs) leads to activation of adenylyl cyclase and synthesis of the second messenger cAMPcAMP does not function in signal pathways initiated by receptor tyrosine kinases (RTKs), but other second messengers may be initiated by both GPCRs and RTKscAMP and other second messengers activate specific protein kinasescAMP specifically activates cAMP-dependent protein kinases (cAPKs)

The effects of many hormones are mediated by second messengersCa2+Structural formulas of four common intracellular second messengers. Their abbreviations are indicated.

2nd messengers2nd messengers

-cAMP-IP3 and DAG-calcium

kinasestranscription factorsgene expression

what is signal transduction?Conversion of a signal from one physical or chemical form into another.In cell biology, it commonly refers to the sequential process initiated by binding of an extracellular signal to a receptor and culminating in one or more specific cellular responses.

Protein Laboratory, University of Copenhagen-Protein kinases-Protein phosphatases-Compartmentalization by clustering (lipid rafts/DRD/caveolae) and scaffolding

Cyclases and phosphodiesterases,Protein kinases and phosphatasescAMP can activate proteins directly, e.g. PKA, cAMP-gated channels, etc.ATP can donate P to phosphorylate proteinPhosphatases turn off the signal

Signal Transduction Endocrine, paracrine, and autocrine signals.

SequenceLigand-receptor bindingSignal (first messenger - extracellular)ReceptorSignal transductionTransducer (across membrane)Amplifier (enzyme)Second messenger (cytoplasmic)Second messenger target (PK)Downstream targets3. (Cytoplasmic) cellular response and/or4. (Nuclear) change in gene expression

Types of Cell SignalingDirect cell-cell signaling vs. signaling via secretion

Types of Cell SignalingCell surface receptors vs. Intracellular receptors

Types of Cell SignalingThree forms of signaling by secreted moleculesParacrineSynapticEndocrine

GAP JUNCTION

Chemical Signals (Primary messengers)Are diverse: can be amino acids/derivatives, peptides, proteins, fatty acids, lipids, nucleotides/derivatives.Water soluble ligands bind to plasma membrane receptors.Lipid soluble ligands diffuse across the MB, bind to intracellular receptors.

Receptors Types of receptors:Ion-channel-linked (ligand-gated channels)Plasma membrane G protein-linkedPlasma membrane enzyme-linkedIntracellular, e.g. steroid hormone receptors Binding of ligand causes:change in conformationclustering of receptors/endocytosissignal transduction across the membraneDesensitization results from chronic exposure to a ligand, due to down-regulation of the receptor.Removal of receptor from membraneAlteration to receptor to lower its affinity for ligandAlteration to receptor so that signal cant be transducedCan also lead to drug tolerance, so same effect is not achieved from same dose (e.g. nasal sprays)

Plasma MB receptors: G-Protein linked

Trimeric G proteins are Molecular SwitchesHappens quickly

cAMP pathwaycAMPProtein kinase AATP + Pro ADP + Pr*-PO3(Phosphorylationof target proteins)Cellular response

Protein Kinase A (PKA)PKA composed of 2 regulatory, 2 catalytic subunitscAMP binds regulatory subunitsSubunits break apart and catalytic subunits phosphorylate target proteins.

Inositol-Lipid (IP3-DAG) Pathway(+) phorbolesters

Hormone Actionpeptide and cathecolaminesTSHReffect2ndmessengerT-4TSHTSHRprotein

Hormone ActionSteroid, ThyroidT-3TBG-receptorsIncreased HRT-3T-3R

Cellular responses to cAMP vary among different cell types