Endocrine Physiology

Huawei Liang (梁华为), PhDE-mail: liang.huawei@yahoo.com.cn

Outline

• Endocrine system and Hormone• Hormone types• Hormone synthesis, storage, release,

transport, clearance and action modes• Characteristics of hormones• Regulation of Hormone Secretion• Mechanisms of hormone action

Endocrine System• One of the two major communication systems in

the body– Have much longer delays– Last for much greater lengths of time

• Integrating stimuli and responses to changes in external and internal environment

• Crucial to coordinated functions of highly differentiated cells, tissues and organs

• Endocrine glands

• Endocrine cells

What is a hormone (激素)?

• Definition

– Chemical messenger synthesized by specific endocrine

cells in response to certain stimuli

– Secreted into blood or extracellular fluid

– Affecting the functions of one or more groups of different

cells (target cells)

• Functions

– Regulation of metabolism, growth and development,

water and electrolyte balance, reproduction, and behavior

Types of Hormones

• Amines 胺类激素

– Thyroid hormones, E, NE

• Proteins and polypeptides 多肽/蛋白质类激素

– Pituitary hormones, insulin and glucagon

• Steroids 类固醇激素

– Sex hormones, cortisol and aldosterone

Synthesis of peptide hormones

DNA

前激素原

激素原

Synthesis of steroid hormones

• From cholesterol (胆固醇)

• Not stored

孕烯醇酮

Synthesis of Amine hormones• From tyrosine (酪氨酸)

• Be stored

Hormone Storage and Release

• Thyroid and steroid hormones– Not stored as secretory granules– Transferring through plasma membrane

• Protein and catecholamine hormones– Stored as secretory granules– Released by exocytosis

Hormones are not secreted at auniform rate

• In a pulsatile pattern

• Diurnal (circadian) rhythm:– linked to sleep-wake cycles (cortisol, growth hormone)

Modes of Action

• Endocrine 内分泌 – transmission of a signal from a classic endocrine cell through bloodstream to a distant target cell

• Neurocrine 神经分泌 – hormone is released from a neuron down its axon and then travels via the bloodstream to target cell

• Paracrine 旁分泌 – hormone acts on adjacent cells• Autocrine 自分泌 – hormone is released and acts on

the cell that secreted it. e.g. norepinephrine itself inhibits further release by that cell in the adrenal medulla

A secretion may have several sites of action simultaneously

Example:

• Norepinephrine- Autocrine action

causes negative feedback on secretion.

- Simultaneously, endocrine action causes respiration rate to increase, peripheral blood vessels to constrict, etc.

Hormone Transport

• Peptides and catecholamine– water soluble– dissolve in blood– circulate in blood mainly in free form

• Steroid and thyroid hormones– circulate in blood mainly bound to plasma proteins– the free form is biologically active– the greater binding, the longer half-life

Hormone Clearance

• The half-life of a hormone in blood– Free: min– Binding: mins, hrs, days

• e.g. T4 (6 days); Insulin (0.006 days)• Ways of Clearance

– target cell uptake– metabolic degradation– urinary or biliary excretion

Characteristics of Hormones

• Regulates rate of reaction

• Do not initiate

• Very specific

• Amplification effect– Present in very small quantity

• pg/mL ~ μg/mL

– Interaction between hormones• Synergistic action 协同作用

• Antagonistic action 拮抗作用

• Permissive action 允许作用

– Hormone A must be present for the full strength of hormone B’s effect.

– Up-regulation of one hormone’s receptors by another hormone– the facilitation of the action of one hormone by another

Regulation of Hormone Secretion

• Three types of inputs to endocrine cells that stimulate or inhibit hormone secretion

• Negative feedback 负反馈

– Most common– Occurs when a hormone produces

a biologic effect that, on attaining sufficient magnitude, inhibits further secretion

• Hormone itself feeds back to inhibit its own synthesis

• Regulated product (metabolite) feeds back to inhibit hormone synthesis

– Important for homeostatic control.– Example: Control of blood glucose

by insulin

• Positive feedback 正反馈

– Less common

– Amplify the initial biological effect of the hormone

– Example: Estrogenpositive feedback on LH secretion

Mechanisms of hormone actions

• Hormone action mediated by the specific receptors– A target cell responds to a hormone because it bears

receptors for the hormone

Hormone Receptors

• Structure– Recognition domain binds hormone– Coupling domain generates signal

• Location– cell membrane (e.g. for insulin)– cytoplasm (for steroids)– nucleus (e.g. for thyroid hormone)

• Receptor capacity– exposure to excess hormone down-regulates capacity– low hormone concentration up-regulates capacity

The receptor provides link between a specific extracellular hormoneand the activation of a specific signal-transduction system

• Two general mechanisms of hormone action– Second messengers – enzyme activity ↑↓

(rapid, cytosolic effects)

– Gene expression - enzymes synthesis ↑↓

(slow, nuclear effects)

Mechanisms of Peptide Hormone Action

• G proteins– are GTP-binding proteins– couple hormone receptors to adjacent effector molecule– have intrinsic GTPase activity– have three subunits: α, β, γ– α subunit bound to GDP → inactive G protein– α subunit bound to GTP → active G protein– the effect can be either stimulatory (Gs) or inhibitory (Gi)

• Second messengers– cAMP second message system– IP3 mechanism– Ca2+-calmodulin mechanism

Signal transduction pathway involving adenylate cyclase

Cyclic AMP signaling-sequence of events• The hormone (1st messenger) binds to the membrane receptor; the

membrane receptor changes shape and bind to G protein (GTP-binding protein)

• G protein is activated; binds to GTP (Guanosine 5’- triphosphate) and release GDP

• Activated G protein moves to membrane and binds and activates adenylate cyclase (GTP is hydrolysed by GTPase activity of G protein)

• Activated adenylate cyclase converts ATP to cAMP (second messenger) (if inhibited, no catalysed reaction by AC)

• cAMP is free to circulate inside the cell; triggers activation of one to several protein kinase molecules; protein kinase phosphorylatesmany proteins

• The phosphorylated proteins may either be activated or inhibited by phosphorylation

Adenylyl cyclase forms cAMP,a “second messenger”that activates enzymes used in cellular responses.

The phosphodiesterase (磷酸二酯酶) enzymes “terminate”the second messenger cAMP

The cAMP system rapidly amplifies the responsecapacity of cells: here, one “first messenger” ledto the formation of one million product molecules.

Each protein kinase can catalysehundreds of reactions

PIP-calcium signaling mechanism

This receptor-G-protein complex is linked to and activates phospholipase C, leading to an increase in IP3 and DAG, which work together to activate enzymes and to increase intracellular calcium levels.

PIP-calcium signaling mechanism• A hormone (first messenger) binding to its receptor causes the

receptor to bind inactive G protein• G protein is activated; binds GTP & releases GDP• Activated G protein binds & activates a membrane-bound

phospholipase enzyme;• G protein becomes inactive• Phospholipase splits phosphatidyl inositol biphosphate (PIP2) to

diacylglycerol (DAG) & inositol triphosphate (IP3);• DAG activates protein kinases on the plasma membrane; IP3 triggers

calcium ion release from the ER• Released calcium ions (second messengers) alter activity specific

enzymes’ activity and ion channels or bind to the regulatory protein calmodulin;

• Calmodulin also activates specific enzymes to amplify the cellular response

Ca-calmodulin system

Mechanisms of steroid Hormone Action

• Modulation of gene expression– Steroid hormones bind to intracellular receptors

– The steroid-receptor complex binds to DNA, turning specific genes on or off

Sequence of events for steroid hormone binding

• Steroids are lipid-based and can diffuse into cells easily

• No need for intracellular second messenger

• Mobile receptors– Some steroids bind to a cytoplasmic receptor, which then translocates

to the nucleus

– Other receptors for steroids are located in the nucleus or are nuclear receptor proteins

– In both cases, the steroid-receptor complex formed can then bind to specific regions of DNA and activate specific genes

• Activated genes transcribe into messenger RNA and instruct the cell to synthesize specific enzyme proteins that change the metabolism of the target cell

Summary• Hormone

– Primarily information transferring molecules– Transfer information from one set of cells to another– Travel via the circulation to affect one or more groups of different

cells to elicit a physiological response

• Hormone types– Protein and peptides – Amines– Steroids

• Action modes of hormones– Endocrine– Paracrine– Autocrine – Neurocrine

• Regulation of Hormone Secretion– Negative feedback– Positive feedback

• Mechanisms of hormone action– Mechanisms of Peptide Hormone Action

• Second messenger signaling pathway– cAMP second message system– IP3 mechanism– Ca2+-calmodulin mechanism

– Mechanisms of Steroid Hormone Action• Modification of gene expression

Summary• Terms

– Hormone

– Permissive action

– Hypothalamic regulatory peptide

• Name the hormones secreted by the hypothalamus in humans, and list the main functions of each

General question

• What are the mechanisms of action of

peptide/protein hormones?