bs148h 23 October 2007Read: Text ch 45

• endocrine system• Para-Neuro-Endo Sys• Prostaglandins-COX-Pain • Feedback & Fever• Receptors & 'Meaning‘• Ancient Origins • Classic Hormones• Steroid Hormones• Endocrine Disrupters• Peptide-Protein Hormones• Caffeine - G-coupled• Hypothalamus-Pituitary• Pheromones

The The NeuroNeuroEndocrineEndocrine SystemSystem is an integrated network: is an integrated network: regulates homeostasishomeostasis in the face of perturbations (ex: body temp, posture), initiates adaptive changeadaptive change in response to signals/cues (ex: fever, movement)

PheromonesPheromones are chemical signals to the neuroendocrine sys of other individuals!

They’re all part of a continuum:Hormones from anterior pituitaryanterior pituitary (ACTH, GH, TSH, LH, FSH, PRL, MSH)

under local control by ‘releasing factors’ from hypothalamus (Fig 45.8);‘Hormones’ from posterior pituitaryposterior pituitary (ADH & oxytocin)

secreted by neurons w/ cell bodies in hypothalamus (Fig 45.7);‘Hormones’ from adrenal medullaadrenal medulla (epinephrine & norepinephrine)

are neurotransmitters from modified neural crest cells;

HormonesHormones secreted into bloodby endocrine glandsendocrine glandsact on receptor proteinsreceptor proteinswhich determine consequencesinside target cells; target cells; Table 45.1:“classic hormones”NeurohormonesNeurohormones are secreted into the blood from neurons; ex: ADH from hypothalamic osmoreceptor neurons via posterior pituitary →↑ kidney reabsorption of H2O

ParacrineParacrine signals are local signals to nearby cells; ex: NO & vasodilation; cytokines & leukocyte recruiting, etc

Fig 11.4

Molecular mechanisms of nociceptionnociception. Julius D & A Basbaus 2001 Nature 413:203-210.

… are one of the chemical signals (cytokines) that recruit phagocytes to wounds and potentiatepotentiate painpain - to get your attention.

http://www.uic.edu/labs/mesecar/lecture_2.htm

COX-1 maintains prostaglandin synthesis in the stomach, kidneys, and platelets.

Prostaglandins: Prostaglandins: widespread & diverse group of paracrineparacrine signalssignals1st found in seminal fluid, from prostate: stimulate contraction of uterine smooth muscle {of another person!}

Non-selective NSAIDsinhibit

COX-1&

COX-2

COX-2 inhibitors selectively inhibit COX-2

COX-2 maintains prostaglandin production predominately in inflamed tissue

PGE2 Celebrex ↑ heart attacks

OpiatesOpiates & cannabinoidscan counteract the increase in excitability of the nociceptor.

When nociceptors {pain nerves} are exposed to injury and inflammation, their excitability is altered.The figure highlights the vanilloid receptor VR1 {stimulated by heat & chemicals like capsaicin

to ↑ Na+ influx }ProstaglandinsProstaglandins PGE2 enhance nociceptor excitability:

↑ Na+ influx @ TTX-R

VR1

PGE2

{note: G-coupled}

Editor's Summary9 November 2006A taste for painThree peptides isolated from the venom of the West Indian tarantThree peptides isolated from the venom of the West Indian tarantula ula ......

have been found to promote pain and inflammation have been found to promote pain and inflammation by activating the same neuronal receptor as capsaicin, by activating the same neuronal receptor as capsaicin, the hot component of the hot component of chillichilli pepperspeppers. ...

News and Views: Physiology:Physiology: ChannelledChannelled painpainLesley Anson Full TextThe newly isolated peptides are dubbed 'vanillotoxins'

because of their action on the TRPV1 vanilloid receptor ...{formerly known as VR1}

Letter: Spider toxins activate the capsaicin receptor Spider toxins activate the capsaicin receptor to produce inflammatory painto produce inflammatory pain

J. Siemens et al. Full Text

Why a Diet Rich in Seafood is HealthyWhy a Diet Rich in Seafood is HealthySci. STKE, 17 October 2006Vol. 2006, Issue 357

OmegaOmega--3 fatty acids3 fatty acids, {“essential” polyunsaturated fatty acids}{omega-3s must be obtained from food ... such as cold-water fish including tuna, salmon, and mackerel... in dark green leafy vegetables, flaxseed oils, and certain vegetable oils.} have been associated with beneficial health effects.

One mechanism for their antitheir anti--inflammatory effect is via inflammatory effect is via competitive inhibition of the enzymatic activity of competitive inhibition of the enzymatic activity of cyclooxygenasecyclooxygenase (COX), (COX), which is the ratewhich is the rate--limiting step in the biosynthesis of prostaglandins.limiting step in the biosynthesis of prostaglandins.

Massaro et al. (2006 Proc. Natl. Acad. Sci. U.S.A. 103, 15184) report that exposure of vascular endothelial cells exposure of vascular endothelial cells to the omega-3 fatty acid docosahexaenoate (DHA) for periods long enough for it to be incorporated into cellular membranes inhibits the ... expression of inhibits the ... expression of COXCOX--22 and prostaglandin production and prostaglandin production in response to the in response to the proinflammatoryproinflammatory signal interleukinsignal interleukin--1 (IL1 (IL--1 ).1 ). ...

Bacon That's Good For You? Researchers Create Pigs Bacon That's Good For You? Researchers Create Pigs That Produce HeartThat Produce Heart--healthy Omegahealthy Omega--3 Fatty Acids3 Fatty AcidsScienceDaily (Mar. 27, 2006)... representing the first cloned transgenic livestock

that can make the beneficial compound.

PhytochemistryPhytochemistry:: IbuprofenIbuprofen--like activity in extralike activity in extra--virgin olive oilvirgin olive oilBeauchamp et al. Nature 437, 45-46 (1 September 2005) Newly pressed extraextra--virgin olive oil containsvirgin olive oil contains oleocanthaloleocanthal —

a compound whose pungency induces a strong stinging sensation in the throat, not unlike that caused by the non-steroidal anti-inflammatory drug ibuprofen.

The bitterness of certain compounds is correlated with their pharmacological activity ... we therefore tested whether oleocanthal might mimic the pharmacological effects

of ibuprofen, a non-selective inhibitor of cyclooxygenase enzymes COX-1 & COX-2.We show here that ... oleocanthaloleocanthal acts as a natural antiacts as a natural anti--inflammatory compoundinflammatory compound

that has a potency and profile strikingly similar to that of ibuthat has a potency and profile strikingly similar to that of ibuprofen.profen.... both these molecules inhibit the same ... both these molecules inhibit the same cyclooxygenasecyclooxygenase enzymes enzymes

in the prostaglandinin the prostaglandin--biosynthesis pathway.biosynthesis pathway.A Mediterranean diet rich in olive oil, is believed to confer various health benefits,

some of which seem to overlap with those attributed to non-steroidal anti-inflammatory drugs.

Our discovery of COX-inhibitory activity in a component of olive oil offers a possible mechanistic explanation for this link.

Thursday 01 September 2005, 16:03 Makka Time,Have a headache? No aspirin or ibuprofen handy? Try some olive oHave a headache? No aspirin or ibuprofen handy? Try some olive oil il --

Scientists have just found out what gourmets have always known - that there is something special about fresh extra-virgin olive oil.

Fever is an adaptive & regulated rise of temperatureFever is an adaptive & regulated rise of temperaturemediated by paracrineparacrine signalssignals (cytokine interleukinsinterleukins) released from macrophagesthe body behaves as if its thermostat has been reset at a hithe body behaves as if its thermostat has been reset at a higher temperaturegher temperature.

which then release ‘cytokines’incl. interleukins IL-1 & IL-6. into local tissue and circ. sys.Locally: recruit immune cells & inflammationAt neurons in anterior hypothalamus which regulate body temp ‘set point’: act as ‘endogenous pyrogens’by increasing synthesis of prostaglandin E2 (PGE2)which acts on hypothalamic neurons in a way that increases the regulated temperature 'set point'. The new setpoint is maintained by heat regulating mechanisms NOTE: ShiveringShivering as fever starts: body temp is below new set point.

Fever 'breaks'Fever 'breaks' with sweating & vasodilationwhen the set point goes back to normal and the body tries to cool down at the end of the illness.

Aspirin reduces fever by inhibiting the synthesis of prostaglandins in the hypothalamus.

Fever is beneficialFever is beneficial; the increased temp accelerates immune responses,incl. antibody production, & inhibits bacterial multiplication by stimulating liver and spleen to sequester iron needed by bacteria..

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Bits of bacterial antigen (LPS endotoxin) are phagocytosedby macrophage leucocytes.

Chemical Signals and their modes of action (see ch 11)

The distribution of receptors across tissues determines which cells ‘get the message.’The The ‘‘meaningmeaning’’ of the message depends on the biochemistry of the receiving celof the message depends on the biochemistry of the receiving cell l

-- not on the hormone per se.not on the hormone per se.

A signal moleculesignal molecule has a specific shape {the ‘key’}that is recognized by the signal’s target cellswhen the signal molecule binds to a receptor proteinreceptor protein, that is in the plasma membranein the plasma membrane of the target cellof the target cell

or located inside the target celllocated inside the target cell. {the ‘lock’}The binding of a signal molecule to a receptor protein

triggers events within the target cell--signal transductionthat result in a response, a change in the cell’s behavior.

Cells are unresponsive to a signal if they lack the appropriate receptors.

Nicotinic acetylcholine

Skeletal Motor neuron

AcetylcholineAcetylcholineParasympathetic:

vagus

Adrenal epinepherineepinepherine (aka adrenalin)

InsulinInsulin through the ages: Phylogeny of a growth promoting and metabolic regulatory hormone.a growth promoting and metabolic regulatory hormone.Chan SJ, Steiner DF. AMERICAN ZOOLOGIST 40 (2): 213-222 APR 2000

Many human hormones are ancient & widespread across phyla;Many human hormones are ancient & widespread across phyla;it is the targets and meaning that have evolved.it is the targets and meaning that have evolved.

…… insulin is an evolutionarily ancient hormone which is present iinsulin is an evolutionarily ancient hormone which is present in all n all metazoametazoa. … in invertebrates the insulin-like peptides … promote tissue growth … in vertebratesvertebrates the growthgrowth function has been subsumed by IGFIGF-I and -II

while insulininsulin … primarily a metabolic regulatory hormonea metabolic regulatory hormone. {ancestral insulin gene duplicated & diverged into IGF’s = insulin-like growth factors}The gene duplication and divergence events necessary for this development probably occurred early during vertebrate evolution

Endocrine hormonesEndocrine hormones: lipid-soluable: (1) steroids, from cholesterol + thyroxine(see Table 45.1) water-soluable: (2) polypeptides < 100 amino acids

(3) glycoproteins > 100 amino acids + a carb.(4) amines from tyrosine

melatonin

insulin, glucagon (fig 45.12)

thyroxine, calcitonin

posterior: ADH, oxytocinanterior: GH, ACTH, PRL,MSH

TSH,LH,FSH

medulla: epinepherinenorepinephrine

cortex: aldosterone,cortisol

estrogens,progesterone

androgens

mysterious ‘thymosins’important in early development of the immune system

parathyroidhormone

Hypothalamus: ‘releasing hormones’(control anterior pituitary – fig 45.8)

+ many new, non-traditional signaling moleculesthat fall between endocrine & paracrine,ex: atrial natriuretic hormone (heart right atrium),

erythropoietin (kidneys), Vitamin D (skin) ...

Supplemental stimulationof existing receptorsupregulates existing genes for muscle proteins{-FB ‘side-effects’ later}

FatFat--soluablesoluable steroidssteroids (and thyroid hormones) diffuse through lipid plasma cell membrane, receptor proteins are inside the cell.

The hormone-receptor complex acts as a transcription factora transcription factor,binding to specific sites in the DNAstimulating or repressing the transcription of specific genesinto new protein in the cytoplasm.

note: lipid-soluablemeans water-insoluable;a carrier protein suspends these in aqueous plasma

BPA is used in the manufacture of plastics and resins ... used in milk and food containers, baby formula bottles ... dental resins ...

BPA leaches from these materials ...

... wildlife and humans are affected by environmental exposure to hormonally active chemicals at levels previously considered to be irrelevant.

EU shifts endocrine disrupterendocrine disrupter research into overdriveLorenz S. SCIENCE 300 (5622): 1069-1069 MAY 16 2003 The European Union is embarking on a massive new effort

to pinpoint the harmful effects of hormonehormone--mimicking chemicalsmimicking chemicals. ...

Endocrine disruptors and reproductive health: The case of Endocrine disruptors and reproductive health: The case of bisphenolbisphenol--AAMaffini MV et al. Molecular and Cellular Endocrinology 254: 179-186 JUL 25 2006

BPA, one of the most ubiquitous endocrine disruptors ... binds both nuclear estrogen receptor (ER) α & β& plasma membrane ERs

{recently discovered}.... found in 95% of urine samples, found in 95% of urine samples,

in maternal & fetal tissue in maternal & fetal tissue & in the milk of nursing mothers& in the milk of nursing mothers...

{data mostly from mice}

Transient exposureTransient exposure of a gestating female rat ... to the endocrine disruptorsto the endocrine disruptorsvinclozolin (an antiandrogenic compound): a commonly used fungicide ...

metabolized into compounds with high affinity to androgen receptors, or methoxychlor (an estrogenic compound): a pesticide to replace DDT;

metabolized into active compounds with ERα (estrogen receptor α) agonist, ERβ antagonist, and anti-androgenic activity

induced an adult male phenotype in the F1 induced an adult male phenotype in the F1 {next} generation generation of decreased of decreased spermatogenicspermatogenic capacity (cell number and viability) capacity (cell number and viability) and increased incidence of male infertility.and increased incidence of male infertility.

News of the Week 3 June 2005: Vol. 308. no. 5727, pp. 1391 - 1392Endocrine Disrupters Trigger Fertility Problems Endocrine Disrupters Trigger Fertility Problems in Multiple Generationsin Multiple Generations

A fungicide and a pesticide known to be toxic to animals, have an even darker side: On page 1466, researchers report that the two chemicals cause fertility defects

in male rats that are passed down to nearly every male in subsequent generations.Epigenetic Epigenetic TransgenerationalTransgenerational Actions of Endocrine Disruptors Actions of Endocrine Disruptors

and Male Fertility and Male Fertility Anway et al. Science 3 June 2005: 1466-1469. [[Full Text]

These effects were transferred through the male germ line to nearly all males of all subsequent generations examined.

The effects correlate with altered DNA altered DNA methylationmethylation patterns in the germ linepatterns in the germ line. The ability of an environmental factor The ability of an environmental factor

to reprogram the germ line to reprogram the germ line {DNA {DNA ““imprintingimprinting””} } has significant implications has significant implications

for evolutionary biology and disease etiology. for evolutionary biology and disease etiology.

WaterWater--soluablesoluable (polar, non(polar, non--steroid) hormones steroid) hormones bind to receptor proteins on the surface of the lipid plasma membrane.

Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors.

Pin JP et al 2003 Pharmacology & Therapeutics 98:325-354. GG--proteinprotein--coupled receptors (coupled receptors (GPCRsGPCRs)) ... ... one of the largest gene families in the animal genome one of the largest gene families in the animal genome ... members have been identified in ancient organisms, such as slime molds (Dictyostelium) and sponges. {see Fig 11.7: - up to 60% of all medications

act on G-protein-coupled receptors}

Signal-receptor binding on outsidealters the ‘tail’ of the receptor inside, setting off a cascade of biochemistry inside, often involving phosphorylation …

… generally changes the metabolism of cellsbut can alter transcription.

see ch 11 for more info on receptors & transduction

CaffeineCaffeine, an alkaloid … in cola nuts, coffee, tea & other plantsAlkaloidsAlkaloids are nitrogeneous secondary compounds

that plants produce to poison herbivores. The LD-50 for coffee varies from 50 to 200 cups.

http://web.sfn.org/content/Publications/BrainBriefings/adenosine.html

Adenosine and SleepAdenosine and Sleep… adenosine {a neurotransmitter,

but also a paracrine signalproduced by active tissues from degraded ATP} promotes sleep.

{note double - : caffeine inhibits inhibition of adenylyl cyclase by adenosine}

Caffeine has a withdrawal syndrome featuring headache and nausea.

Caffeine is used to relieve headaches.

less cAMP:

adenosine

Note the - !

-

sleepy, less dopamine in brain{dopamine & addiction later}

Caffeine'sCaffeine's stimulating characteristics stem from its action as an ‘adenosine disrupter:’it prevents adenosine from binding to cells at a G-coupled receptor)

X The HypothalamusHypothalamus is ‘The Master Puppeteer,’but monitors feedback & other inputs from brain.{Figs 45.7 & 45.8}

PosteriorPosterior Pituitaryis an extension of the hypothalamus.

AnteriorAnterior Pituitary controlled byreleasing factors from hypothalamusvia portal (double) capillary sys.

Alcohol inhibits ADH secretionAlcohol inhibits ADH secretion, the kidneys fail to retain water and the person excretes large volumes of urine.

THE PHYSIOLOGY OF THE HANGOVERhttp://ist-socrates.berkeley.edu/~jmp/LO2-HCG.html

{ADH is also a neurotransmitter in brainaka vasopressin – more later}

Consider the role of testosterone in the the --FB loop from testes to hypothalamusFB loop from testes to hypothalamus,that regulates secretion of gonadotropins FSH & LH, that regulate gonads.

Testicular atrophy !Testicular atrophy !What do you suppose happens when blood testosterone

(or mimic) levels are raised by external supplements?

AnabolicAnabolic--androgenic steroids (AAS),androgenic steroids (AAS),are synthetic derivatives of testosterone. used by body builders and weightlifters to increase lean muscle and decrease fat

http://www.dotpharmacy.com/upanabol.html

The hypothalamus & anterior pituitary hypothalamus & anterior pituitary monitor feedbackmonitor feedback

Fig 14.14

Hormone therapy: A dangerous elixir?Nature 431, 500 - 501 (30 September 2004)

Testosterone therapy jacks up vigour, sex drive and mental acuity - or so proponents claim. But are those who experiment with this potent sex hormone

gambling with their health? … testosterone replacement might increase the likelihood

that latent cancerous cells in the prostate gland will transform into tumours. …

Testosterone changesTestosterone changesduring vicarious experiences during vicarious experiences of winning and losing of winning and losing among fans at sporting eventsamong fans at sporting events

Bernhardt PC, Dabbs JM, Fielden JA, et al.PHYSIOLOGY & BEHAVIOR 65 (1): 59-62 AUG 1998 ... mean testosterone level mean testosterone level

increased in the fans of winning teams and increased in the fans of winning teams and decreased in the fans of losing teams. decreased in the fans of losing teams.

(cortisol)

‘‘Fight or flightFight or flight’’

Interactions Between Mental States, Physiology, and Immunity A Dynamic Psychoneuroimmunologic Network

by Duncan Smith-Rohrberg

http://hcs.harvard.edu/~husn/BRAIN/vol7-spring2000/neuroimmuno.

Immunosuppression w/ steroids (ex Prednisone) is used for treatment of inflammation, allergy, MS & other autoimmune problems

(aldosterone)

Adrenal medulla Adrenal cortex

Many insects use pheromones to attract matesMany insects use pheromones to attract mates (usually female signaling to male)We have figured out how to synthesize many of these, especially for ‘pests,’and use them to lure one sex (usually males) into traps.

Safer Japanese Beetle TrapsBe prepared for the arrival of Japanese beetles

with this dual-scented lure trap. …The floral lure attracts the females while the pheromone lure brings in the males.

PheromonesPheromones are chemical signals released by an individual into the environment which affect the physiology or behavior of other members of the same species.

Human sex Human sex pheromones?pheromones?

Here we investigate whether humans produce compounds that regulate a specific neuroendocrine mechanism in other people without being consciously detected as odours(thereby fulfilling the classic definition of a pheromone).

Axillary (underarm) compounds from the same donors which were collected later in the menstrual cycle (at ovulation) had the opposite effect:

they delayed the luteinizing-hormone surge of the recipients and lengthened their menstrual cycles.

We found that odourlessodourless compounds from the armpits of womencompounds from the armpits of womenin the late follicular phase of their menstrual cycles accelerated the preovulatory surge of luteinizing hormone of recipient women and shortened their menstrual cycles.

{This seems to be the mechanism that synchronizes menstrual cycles in groups}

Regulation of ovulation by human pheromones.Regulation of ovulation by human pheromones.Stern K, McClintock MK XNATURE 392: (6672) 177-179 MAR 12 1998

… this study provides definitive evidence of human pheromones.

we extracted underarm secretions from pads worn by men and placed the extract under the nose of womenwhile monitoring serum LH and emotion/ mood.

Male Male axillaryaxillary extracts contain pheromonesextracts contain pheromonesthat affect pulsatile secretion of luteinizing hormone and mood in women recipients.Preti G, et al. Biology of Reproduction 68 (6): 2107-2113 JUN 2003

Pulses of LH are excellent indicators of the release of GnRH from the hypothalamus.

In women, the positive influence of GnRH on LH affects the menstrual cycle and fertility.

Here we show that extracts of male male axillaryaxillary secretionssecretionshave a direct effect upon LHhave a direct effect upon LH--pulsing and mood of women.pulsing and mood of women.

In our subjects, the putative male pheromone(s) advanced the advanced the thethe next peak of LHnext peak of LH after its application, reduced tension, and increased relaxationreduced tension, and increased relaxation.

Sniffing a human sex-steroid derived compound affects mood and autonomic arousalin a dose-dependent manner. Bensafi et al. 2004 Psychoneuroendocrinology 29:290-1299.

… sniffing different concentrations of … 4,16-androstadienandrostadien-3-one (AND) …increased positive mood in women compared to men, and had sympatheticsympathetic--like effects in womenlike effects in women and parasympatheticparasympathetic--like effects in menlike effects in men.

Brain response to putative pheromones in homosexual men.Brain response to putative pheromones in homosexual men.Savic et al. PNAS 2005 102: 7356-7361 The testosterone derivative 4,16-androstadien-3-one (ANDAND)

and the estrogen-like steroid estra-1,3,5(10),16-tetraen-3-ol (ESTEST) are candidate compounds for human pheromones.

ANDAND is detected primarily in male sweat, whereas ESTEST has been found in female urine. In a previous positron emission tomography study, we found that smelling ANDAND and ESTEST activated regions covering

sexually dimorphic nuclei of the anterior hypothalamus, and that this activation was differentiated with respect to sex and compound.

In the present study, the pattern of activation induced by AND and EST was compared among homosexual men, heterosexual men, and heterosexual women.

In contrast to heterosexual men, and in congruence with heteroseIn contrast to heterosexual men, and in congruence with heterosexual women, xual women, homosexual men displayed hypothalamic activation in response to homosexual men displayed hypothalamic activation in response to ANDAND.

Maximal activation was observed in {areas} highly involved in sexual behavior. Common odors were processed similarly

in all three groups of subjects ...These findings show that our brain reacts differently

to the two putative pheromones compared with common odors, and suggest a link between sexual orientation a link between sexual orientation and hypothalamic neuronal processesand hypothalamic neuronal processes.