Chapter 45: CHEMICAL SIGNALS IN ANIMALS

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

But they’re all part of a continuum:• Hormones from posterior pituitary (ADH & oxytocin) secreted by neurons w/ cell bodies in hypothalamus (Fig 45.6a); • … from anterior pituitary under local control by ‘releasing factors’ from hypothalamus (Fig 45.6b);• adrenal medulla secretes neurotransmitters (epinephrine & norepinephrine) from modified neural crest cells (Figs 45.11-12); etc.

C &

R F

ig 1

1.3

It is conventional to categorize chemical signals & modes of action

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

Prostaglandins Prostaglandins (a group of related compounds). Named from discovery in semen (fluids from prostate): stimulate contraction of uterine smooth muscle - pump sperm up … Note: this particular function is a chemical signal to another individual.

Prostaglandins are one of the Chemical Signals (cytokines) that recruit phagocytes to wounds and potentiate painpotentiate pain - to get your attention, so you’ll protect wound while it heals.

Potentiates painpain by sensitizing nearby ‘pain receptor’ neurons (nociceptors): more responsive to slightest pressure.

Cyclooxygenases COX1 & COX2 catalyze the final step in prostaglandin synthesis. NonSteroidal Anti-Inflamatory DrugsNonSteroidal Anti-Inflamatory Drugs, or NSAIDs, act by inhibiting cyclooxygenases generally – both COX1 & COX2 . The best known NSAID is aspirin. Prostaglandins from COX 1 act to suppress acid secretion in the stomach and to promote the formation of a protective mucus coating on the stomach wall, so general cyclooxygenase inhibitors, such as aspirin, cause pitting and bleeding of the stomach wall.

http://elfstrom.com/arthritis/nsaids/actions.htmlCopyright ©1997 David Elfstrom

PGE2

COX-1 maintains prostaglandin synthesis in the stomach, kidneys, and platelets. selective inhibition of COX-2, avoids all adverse GI events from COX-1 inhibition …Also COX-2 does not inhibit platelet aggregation, which is beneficial in patients when bleeding is a concern.

http://www.ncpanet.org/CONTEDU/rheumatoid.html

COX-2 INHIBITORS Celecoxib (Celebrex®), are a new class of drugs that selectively inhibit cyclooxygenase 2. COX-2 maintains prostaglandin production predominately in inflamed tissue and joints.

DysmenorrheaDysmenorrhea … More commonly referred to as crampscramps, is painful menstruation caused by abnormal uterine contractility …Dysmenorrheic women produce more prostaglandinsprostaglandins in the endometrium and menstrual fluids than those without dysmenorrhea. Cyclooxygenase inhibitors such as aspirin, naproxen or ibuprofen prevent the formation of prostaglandins and relieve the symptoms of dysmenorrhea.

Q: How does Mifeprex {RU486} work? A: Mifeprex blocks progesterone, a hormone necessary for a pregnancy to continue. You take Mifeprex followed by a prostaglandin, misoprostol, which causes uterine contractions that help to end pregnancy.

Nitric Oxide NONitric Oxide NO is a free radical gas that is synthesized as needed (can’t be stored) to diffuse and signal neighboring cells. {see http://www.pasteur.fr/applications/euroconf/nitric-abstracts.html#01}

Oxygen-deprived tissues release small amounts of NONO; dilates smooth muscle of arterioles and capillary sphincters and allows increased blood/oxygen delivery {recall Viagra}

Pro-inflammatory cytokines stimulate production of NONO in vascular endothelium & smooth muscle, resulting in vasodilation & in extreme cases ‘toxic shock’

NONO provides ‘back-talk,’ +FB (Long Term Potentiation) back across synapses, which might be an important mechanism in learninglearning and memorymemory …

+

Macrophages use heavy doses to kill bacteria.

The serious side of laughing gas!

http://neuroscience.about.com/science/neuroscience/library/blNo.htm

nitric oxidenitric oxide plays a role in plays a role in LTP {Long Term Potentiation - learning & memorylearning & memory} …In this model, glutamate released from a presynaptic terminal binds to postsynaptic NMDA receptors {non-methyl-D-aspartate receptors} causing an influx of calcium ions (Ca++). The increased Ca++ concentration leads to activation of NO synthase, which results in a production of nitric oxide (NO).nitric oxide (NO).

NONO then defuses to surrounding tissue, including the presynaptic release terminal, where it binds to and activates guanylate cyclase. This sets into motion a biochemical cascade that results in increased glutamate release from the presynaptic terminal. {+FB ‘reverberation’ that might facilitate long-term activation of the synapse}Figure adapted from: Holscher C, 1997. Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity. Trends Neurosci. 20:298-303.

Chemical Signals and their modes of action

The distribution of receptors across tissues determines which cells ‘get the message.’

The ‘meaning’ of the message depends on the biochemistry of the receiving cell - not on the hormone per se.

Parasympathetic:vagus

Parasympathetic:Does the name Pavlov

ring a bell?

Nicotinic acetylcholine

Motor neuron

A signal moleculesignal molecule has a specific shape that is recognized by the signal’s target cells when the signal molecule binds to a specific receptor proteinreceptor protein, which is either built into the plasma membranebuilt into the plasma membrane of the target cellof the target cell or located inside the target cellor located inside the target cell. The binding of a signal molecule to a receptor protein triggers events within the target cell--signal transduction that result in a response , a change in the cell’s behavior. Cells are unresponsive to a signal if they lack the appropriate receptors.

InsulinInsulin through the ages: Phylogeny of 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; it is the targets and meaning that have evolved.

Abstract:… DNA techniques have identified insulin-like peptide genes in invertebrates, including Insects, molluscs and nematode and these findings clearly establish that insulin is an evolutionarily ancient hormone which is present in all metazoainsulin is an evolutionarily ancient hormone which is present in all metazoa. … in invertebrates the insulin-like peptides function … to promote tissue growth … in vertebrates the growth function has been subsumed by IGF-I and -II while insulin … primarily a 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 in the transition from protochordates, represented by extant amphioxus, to primitive jawless vertebrates, represented by extant lamprey and hagfish.

The receptors for water-soluable (non-steroid) peptide hormones (Table 45.1) are usually on the surface of the fatty plasma membrane.

Signal-receptor binding on outside alters the ‘tail’ of the receptor inside, setting off a cascade of biochemistry inside, often involving phosphorylation …{see ch 11 for molecular-cellular details:Note this ex: G-protein, adenylyl cyclase & cAMP}

… generally changes the metabolism or configuration of cells

C & R Fig 11.13See other examples

in Ch 11

CaffeineCaffeine, an alkaloid … in cola nuts, coffee, tea, cacao beans and other plants AlkaloidsAlkaloids 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 {like NO, a vasodilator & ‘neuromodulator’ produced by active tissues} promotes sleep.Investigations into the relationship between adenosine and sleep surged following the discovery that caffeine's stimulating characteristics stem from its ability to prevent adenosine from binding to cells and launching distinct actions.

Caffeine has a withdrawal syndrome featuring headache and nausea. Caffeine is used to relieve headaches.

Adenosine, adenosine receptors and the actions of caffeine. Fredholm, B. B. 1995. Pharmacological Toxicology 76,93-101.

adenosine

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

less adrenal epinephrine

less cAMP:

Note the - !

{note double - : caffeine inhibits inhibition of adenylyl cyclase & cAMP}

The receptor molecules for fat-soluable steroidsfat-soluable steroids (and thyroid hormones) are inside the cell.

The hormone-receptor complex acts as a transcription factora transcription factor, binding to specific sites in the cell’s DNA stimulating or repressing the transcription of specific genes.New mRNA is then translated into new protein in the cytoplasm.

Supplemental stimulationof existing receptorsupregulates existing genes for muscle proteins

An endocrine disrupterendocrine disrupter is an agent that has the potential to interfere with the production, release, transport, action or elimination of hormones.

… endocrine disrupter chemicals and estrogen receptor … Kuramitz H, Natsui J, Sugawara K, Itoh S, Tanaka SANALYTICAL CHEMISTRY 74 (3): 533-538 FEB 1 2002A new electrochemical screening method for endocrine disrupting chemicals (EDCs) was developed. The binding affinity between EDC and the estrogen receptor (ER) was … was evaluated … Bisphenol A, p-nonylphenol and p,p'-DDT were used as test compounds. All test compounds demonstrated some ability to bind with ER.

It has been hypothesised that increased incidence of hormone-sensitive cancers, decreased sperm counts in men, {early puberty in girls} and compromised gonadal functionality in wildlife are due to exposure to substances possessing estrogenic activity.

Several environmental pollutants have binding affinities for both androgen receptor and estrogen receptor alpha.Satoh K, et al. J HEALTH SCI 47 (5): 495-501 OCT 2001

The ‘Classic’ Glands & Hormones

Learn them!

The HypothalamusHypothalamus is ‘The Master Puppeteer,’ but monitors feedback, as well as other inputs from brain.

Anterior Pituitary (from endoderm) controlled by releasing factors from hypothalamus.

EndogenousOpiates

pg 964

Posterior Pituitary is extension of hypothalamus.

http://www.xrefer.com/entry/149561

Endogenous Opiates:Endogenous Opiates: A group of naturally occurring, opiate-like peptides produced by the brain. They play important roles in control of emotional behaviors such as pain, anxiety, fear, and related affective states produced by pain.

All classes of opioid receptor share key similarities. Activation of any type of opioid receptor inhibits adenylate cyclase {like adensoine}. They are G protein-linked receptors in the plasma membrane of neurons. Once the receptors are bound, a portion of the G protein is activated …The G protein moves within the membrane until it reaches its target …These targets alter protein phosphorylation and/or gene transcription. …

Opioidergic neuronsOpioidergic neurons are particularly concentrated in the ventral tegmental area VTA … an important tract in the limbic system. The VTA passes messages passes messages toto clusters of nerve cells in the nucleus accumbens and the frontal cortex … the brain's primary reward pathwaythe brain's primary reward pathway, the mesolimbic dopaminedopamine system. Its neurons are called dopaminergic because dopamine is manufactured, transported down the length of the neuron, and packaged for release into the synapses.

http://www.uchospitals.edu/news/Nicadd.htmlNicotine {another plant alkaloid to poison herbivores} appears to cause addiction by strengthening the excitatory connections to the neurons that make dopamine, {pg 1037} which are found in the Ventral Tegmental Area (VTA) of the brain reward center. Thus, the neurons are more excited, which means that more dopamine is released within the reward areas.

Reduced dopamine D1 receptor binding in the ventral striatum of cigarette smokers.Dagher A, et al. SYNAPSE 42 (1): 48-53 OCT 2001Abstract: …Animal and human studies suggest that chronic administration of addictive drugs may lead to impaired dopamine neurotransmission in the nucleus accumbens. We measured DI receptor density in 11 smokers and 18 nonsmokers using positron emission tomography and the D1 receptor ligand [C-11]SCH 23390 {a label}. … there was a significant reduction in [C-11]SCH 23390 binding potential in smokers compared to nonsmokers in the striatum, most prominently in the ventral striatum. Such a hypodopaminergic state may play an important role in sustaining nicotine-seeking behavior. {need hyperstimulation of few remaining dopamine receptors in ‘pleasure centers’?}Alternatively, an inherited reduction in dopamine receptors in the striatum may be associated with an increased risk of addictive behavior.

… then target cells compensate for over-stimulation by reducing dopamine receptors:

blood glucoseconcentration

in pancreas

‘normally’ 90mg/100ml

error signal <0

comparator

push up

thing being controlled

pull down

setpoint

+ -

error signal >0

Negative Feedback

insulin from beta cells …

glucagon from alpha cells …

+

-

Push-Pull regulation:Push-Pull regulation:

Insulin-dependent diabetesInsulin-dependent diabetes (aka Type I; Juvenile onset):autoimmune destruction of beta cells{why can’t we eat insulin pills?}

Non-insulin-dependent diabetes Non-insulin-dependent diabetes (aka Adult onset):age-obesity-related loss of insulin receptors

Anabolic-androgenic steroids (AAS),Anabolic-androgenic steroids (AAS), are synthetic derivatives of the male sex hormone, testosterone. AAS are used by body builders and weightlifters to increase both lean muscle mass and strength and to decrease body fat,

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

Consider the role of testosterone in the -FB-FB 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?

(cortisol)

‘Fight or flight’ Immunosuppression with steroids (especially Prednisone ) is used for treatment of inflammation,allergy, MS & other autoimmune problems

Neuroendocrine function and chronic inflammatory stresschronic inflammatory stress.Harbuz M EXPERIMENTAL PHYSIOLOGY 87 (5): 519-525 SEP 2002Abstract:The factors regulating susceptibility and severity of autoimmune diseases are poorly understood. That neuroendocrine factors are critical modulators in this regard is self-evident. … there are major gender differences in susceptibility with women at greater risk than men of, for example, rheumatoid arthritis (RA) and multiple sclerosis (MS). The hypothalamo-pituitary-adrenal (HPA) axis has rightly attracted a considerable amount of attention. Of particular interest has been the hypothesis that susceptibility to autoimmune disease may be related to susceptibility to autoimmune disease may be related to an impaired responsiveness of the HPA axis; that is, an impaired responsiveness of the HPA axis; that is, an inability to mount an appropriate cortisol response an inability to mount an appropriate cortisol response with which to down-regulate the immune system with which to down-regulate the immune system might allow the immune system to rampage unchecked and attack self. This hypothesis links regulation of the release from the adrenal gland of the potent anti-inflammatory glucocorticoids to the disease process. The hypothesis proposing a link between a hyporesponsive HPA axis and susceptibility to {autoimmune} disease is compelling. …

{Does this imply that women aren’t stressed-out enough?!}

Glucocorticoid receptor variantsGlucocorticoid receptor variants: clinical implications.DeRijk et al. J Steroid Biochem & Molecular Biol 81(2):103-122 JUN 2002Abstract:Following exposure to stress, cortisol is secreted from the adrenal cortex under the control of the hypothalamic-pituitary-adrenal axis (HPA-axis). Central in the regulation of the HPA-axis is a two tied corticosteroid-receptor system, comprised of high and low affinity receptors, the mineralocorticoid receptor (MR) & the glucocorticoid receptor (GR)glucocorticoid receptor (GR) … these receptors mediate the effects of cortisol during stress …Cortisol modulates gene-expression of corticosteroid-responsive genesCortisol modulates gene-expression of corticosteroid-responsive genes …Mutations in the GR-gene are being associated with corticosteroid resistanceMutations in the GR-gene are being associated with corticosteroid resistance … Several GR-gene variants and single nucleotide polymorphisms (SNP) in the GR-gene have been identified which are relatively common in the human population. The GRbeta-variant, for example, has been proposed to influence corticosteroid-sensitivity and … in particular asthmaasthma. … we propose that a common underlying defect in these complex disorders is a disregulation of the HPA-axis, especially during stress. The clinical implication is that the regulation of the HPA-axis should be envisioned as a primary target of new drugs for the treatment of stress-related disorders.

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

C&R Fig 11.1Haploid yeast cells can exist as one of 2 different mating types: a or . MATa cells recognize and mate with MAT cells, and vice versa. The difference is in a single locus (the MAT locus) … MATa cells: secrete a-factor & respond to -factorMAT cells: secrete -factor & respond to a-factorThe pheromonepheromone signals that cell of the opposite mating type is nearby and prepares the cell for the mating event — culminates in cellular and nuclear fusion to make a diploid zygote,

A haploid cell can switch its mating type to the opposite type by using an endonuclease that recognizes … the MAT locus and cleaves it. There are "spare copies" of the mating type loci on either end of Chromosome III:

Right end: HMRa = copy of MATaLeft end: HML = copy of MAT

After the MAT locus is cut, one of these copies will be used to repair the locus. Thus, about half the time, it will be repaired to its original state, but about half the time it will be converted to the opposite type.

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 Traps Be 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.

Human sex 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 odourless compounds from the armpits of womenodourless compounds from the armpits of women in 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.

Behavioral and electrophysiological effects of androstadienone, a human pheromoneandrostadienone, a human pheromone.

Grosser BI et al. Psychoneuroendocrinology X25: (3) 289-299 APR 2000Abstract:Androstadienone is the most prominent androstene present on male human axillary hair and on the male axillary skin surface. {armpits} We have previously shown that this volatile steroid is able to simulate the human female vomeronasal organ … resulting in changes in autonomic activity. These effects are gender-specific.

The purpose of the present study was to ascertain whether androstadienone could be considered a human pheromone by altering behavior as well as autonomic function. Forty normal female subjects were randomized in a double-blind manner to receive either control or 100 pg of androstadienone directly to the vomeronasal organ. We report that administration of this steroid under these conditions results in a significant reduction of nervousness, tension and other negative feeling states. Concordant changes were observed in autonomic physiology.

Context-dependent effects of steroid chemosignals on human physiology and mood.Jacob S et al. PHYSIOLOGY & BEHAVIOR 74 (1-2): 15-27 SEP 1 2001… Women's responses were observed only in the sessions run by the male tester …