C2006/F2402 '05 OUTLINE OF LECTURE #16
(c) 2005 Dr. Deborah Mowshowitz, Columbia University, New York, NY. Last update 03/24/2005 09:27 AM .
Handouts: Need 15B, 16A (Homeostasis), 16 B -- Lactation & Stress Response
I. How is a component of the internal milieu regulated?
A. Example #1 -- Regulation of blood glucose. The see-saw view. See handout 15B or Purves 50.19 (50.20).
1. Have a regulated variable -- glucose level in blood
2. Need a sensor (or receptor) -- to measure levels of regulated variable (glucose)
3. Need effector(s) -- to control levels of regulated variable (glucose) -- usually have two effectors that act in opposing ways.
Note: The term "effector" is used differently in molecular biology and in physiology. In physiology, it is usually used to mean "a tissue or organ (like muscle or liver) that carries out an action and thus produces an effect." In this example, the effectors = structures that act to raise or lower the blood glucose. In molecular biology, the term "effector" is usually used to mean "a modulator of protein function." A modulator = a small molecule (like an inducer, enzyme activator etc.) that binds to a protein, alters the shape and/or function of the protein, and thus triggers an effect.
4. Have a set point -- the level the regulated variable (blood glucose) should be. Set point is also some times used to mean the level at which corrections (to raise or lower the value) kick in.
In most cases, there is no difference between these two definitions of set point. In some cases, the desired value (first definition) and the value at which corrections occur (second definition) may be different. For example, there may be two cut-off points-- upper and lower, that bracket the desired level of a regulated variable. At levels above or below the respective cut-off points, messages are sent to the appropriate effectors to take corrective action. The term "critical values" is sometimes used instead of "set points" to describe the cut-off point(s).
5. Negative Feedback -- system responds to negate changes from set point. (In positive f.b., system responds to change by making it bigger and bigger until --> boom!)
6. Value of regulated variable does not remain exactly constant, but stays within narrow limits.
See problem 5-1 & 5-2 a & b.
B. Example #2 -- Regulation of body temperature (in humans) -- the see-saw view (handout 16A)
1. Features not found in glucose case:
a. Multiple sensors in different places (for core and skin temp.)
b. Need separate integrative center (IC).
(1). Role of IC: Compares set-point to actual value, sends appropriate message to effectors.
(2). Sensor/IC function may be combined, as in Glucose example.
(3). Separate IC needed if there are multiple sensors, as in this case.
(4). In this example, IC = hypothalamus (HT)
(5). Role of separate IC: Co-ordinates incoming (afferent) information from sensors; compares set-point to actual value, sends appropriate outgoing (efferent) information to effectors.
2. Different body systems involved as effectors
Action To Raise Temp
Action To Lower Temp
Contraction generates heat (shivering)
Smooth muscle of peripheral blood vessels in skin
Muscles contract; vessels constrict to reduce heat loss
Muscles relax; vessels dilate to increase heat loss
Produce sweat; evaporation increases heat loss
Behavioral (nonphysiological) responses-- put on coat, curl up, etc.
Behavioral (nonphysiological) responses -- take off coat, etc.
3. Cooling vs. Heating -- What can effectors do? Effectors can increase or decrease heat loss; can only increase heat generation. (No air conditioner.) Therefore ability of humans to cope with very cold environments is better than their ability to cope with excessively hot environments.
Try Problem 5-2, c. & 5-5.
C. Body Temperature and the General Case -- The Circuit View -- handout 16A.
1. Signals: System involves more than one cell so signals must be sent using nerves and/or hormones from sensor to effectors. (For comparison: only 1 cell involved in 2 cases of feed back. previously discussed: Fe circuit with Ferritin/Transferrin Receptor or interconversion of glycogen and glucose-1-phosphate in skeletal muscle)
2. Afferent vs Efferent Signals. Bottom half of circuit has two arms -- Afferent information (from sensors in to IC) vs efferent (out of IC --> effectors)
3. Regulation vs Control.
a. Regulation: The variable (glucose level) you wish to keep at an approximately constant level is said to be "regulated."
b. Control: The processes that alter levels of the regulated variable (glucose uptake, release, etc.) are said to be "controlled."
c. What's the difference? The point of the system is to maintain homeostasis of glucose levels, not homeostasis of rates of glucose uptake, release, etc. The value of the regulated variable stays about the same; the rates of the controlled processes -- uptake, release etc. -- can vary as much as necessary to achieve homeostasis of glucose levels.
4. May be multiple effectors and/or sensors.
5. IC (when there are multiple inputs) is nervous tissue or brain.
a. Compares current value to set point; sends appropriate message to effectors.
b. Can adjust set points and/or critical points. Why bother? Fevers & feedforward:
(1). Fevers -- Raise set point for body temperature and critical points for shivering/sweating
Shivering and sweating both kick in at higher temps. (You don't have to cool off as much to start shivering and you need to heat up more to stop sweating.) Raises set point (desired level) & actual level of internal body temperature.
Why fevers? High temperatures prevent bacteria from obtaining iron from host & improve immune function.
(2). Feedforward or anticipation -- Planning ahead. Altering set points and/or critical points to adjust to anticipated factors. (Or you can think of it as just ignoring the usual critical points.) Examples:
Body temperature: Skin temperature affects critical temperature/set points for generating heat and/or shivering. If body is cold, but it's warm outside, shivering can be postponed, saving energy, and you'll still warm up. This is equivalent to lowering (or ignoring) set point/critical points for shivering, not changing set point of internal body temperature. Changes what effectors and what controlled processes you use to warm up, but not the end result.
Secreting insulin when you start to digest food in the stomach, but before the digestion products (glucose, amino acids etc.) reach the blood. This way tissues will be ready to take up the glucose as soon as it enters the blood.
D. What other components of internal milieu are regulated besides glucose, temperature? Many nutrients like amino acids; concentrations of water, salts and ions (Na+, K+ etc.), gases (CO2, O2), waste products, volume & pressure of blood, and pH.
Try Problems 5-3, 5-4 & 5-9 A & B. (BMR = basal metabolic rate).
II. Matching circuits and signaling -- an example: How the glucose circuit works at molecular/signaling level
A. Re-consider the circuit/see saw diagram for homeostatic control of blood glucose levels -- what goes along the arrows, and what happens in the black boxes?
B. What are the effectors?
a. Liver -- carries out both storage and release of glucose so acts as buffer; only organ that can release glucose into blood; takes up glucose without insulin (does not use GLUT 4).
b. Muscle -- stores or releases energy and protein.
c. Adipose -- stores or releases fat/ fatty acids.
d. All three organs co-operate -- for example lactate generated in muscle is not broken down further in muscle -- it is shipped to liver and metabolized further in the liver. (For details see Purves 50-20 (15-21))
C. Mechanism of Action of hormones Involved
a. Receptor: Insulin works through a special type of tyrosine kinase linked receptor; See Purves 15.6 (15.7). Insulin has many affects on cells and the mechanism of signal transduction is complex (activating multiple pathways). In many ways, insulin acts like a GF (it has GF-like effects on other cells; is in same family as ILGF's).
b. Effect on Glucose Uptake.
(1). In resting skeletal muscle & adipose -- mobilizes GLUT 4: In these tissues insulin mobilizes transporter for facilitated diffusion (of glucose) -- GLUT 4 protein -- promotes fusion of vesicles containing the transporters with plasma membrane. No other hormone can cause this effect.
(2). In liver & brain: Brain & liver can take up glucose without insulin -- they do not use GLUT 4. They use different transporters (GLUT 1, 2 &/or 3) located permanently in the plasma membrane.
(a). Brain: Insulin has no affect on glucose uptake in brain.
(b). Liver: Insulin promotes glucose uptake in liver, but not directly. Insulin promotes uptake by increasing phosphorylation and utilization of glucose.
(3). Working skeletal muscle: Insulin is not required for uptake of glucose in working skeletal muscle because exercise mobilizes GLUT4 in skeletal muscle. (Another good reason to exercise.)
c. Other Effects: In many tissues, insulin promotes utilization of glucose
(1). Activates appropriate enzymes for synthesis of storage forms of metabolites -- synthesis of glycogen, fat, and/or protein.
(2). Inhibits enzymes for breakdown of stores.
(3). Can promote breakdown of glucose for energy.
d. Overall: promotes uptake & utilization of glucose.
a. Receptor: Glucagon works through a G protein linked receptor that triggers the cAMP pathway (as for epinephrine). Therefore it activates PKA; see handout 12 B for effect on glycogen metabolism.
b. Effects: Primary effect is on liver; generally promotes production/release of glucose, not uptake or utilization.
c. Receptor triggers same pathway as epinephrine. Note that the same signaling pathway can be used for two different hormones (epinephrine & glucagon).
(1). Epi. & glucagon bind to different receptors, but both receptors activate the same G protein and trigger the same series of events --> cAMP --> etc. so get same response to both hormones in same tissue.
(2). Receptors present on cell surface determine which tissues will respond to each hormone. Muscle has Epi receptors and responds to Epi but not glucagon; liver has receptors for both and responds to both.
(3). Two hormones control same process (glycogen metabolism) for different purposes -- Epi to respond to stress; glucagon to respond to low blood sugar (maintain homeostasis).
(4). Same hormones give different response in liver vs adipose tissue. How? Both hormones trigger production of cAMP and activation of PKA. But different enzymes and processes (glycogen metabolism vs. fat metabolism) available to be controlled by same kinase.
D. Absorptive vs Postabsorptive State -- A more complex view of the circuit (See Purves fig. 50.20 (50.21))
1. What is really being regulated by insulin & glucagon? Really two different things:
a. Maintenance of glucose homeostasis
b. Managing an episodic event (eating) -- this can be considered just another example of homeostasis -- here the 'episodic' nature of eating generates two basic states that must be controlled differently to maintain homeostasis.
→ synthesis & storage of macromolecules; glucose is primary energy source. In this state, right after you eat, the risk is that blood glucose levels will rise too much. Absorptive state is completely dependent on insulin. Insulin affects all three effector organs.
2. There are two main states of food (not just glucose) supply:
a. Absorptive -- anabolic
b. Postabsorptive -- catabolic→ breakdown of macromolecules to release glucose*; fatty acids are primary energy source (except in brain). In this state, between meals, the risk is that blood glucose levels will fall too much. Postabsorptive state is largely caused by lack of insulin; also utilizes glucagon, but stress hormones (cortisol and epinephrine) can fill in for glucagon. Glucagon mainly affects liver.
*Glucose is also assembled in liver from smaller molecules such as lactate (= gluconeogenesis); see texts if you are interested.
For questions on this topic
see problem set 7,
questions 7-22 to 7-25, and 4-14.
To review and to be sure you have this topic straight, fill in the following tables:
|Responds to Insulin?||Responds to Glucagon?||Can Release Glucose to Blood?||Uses GLUT 4||Can take up Glucose w/o Insulin?|
|Skeletal Muscle||+||-||-||+||only when working; not at rest|
|Type of Receptor/signaling pathway|
|Effect on blood glucose -- release or uptake?|
|Effect on glycogen -- synthesis or breakdown?|
|Result of intracellular glucose metabolism -- use it up or generate it?|
|Effect on intracellular glucose production -- inhibit or stimulate?|
III. Lactation: Example of Positive Feedback & Use of Neuronal signals See 15B.
A. Overall Loop: suckling by baby ---> milk ejection ("letdown) --> more suckling --> more milk ejection etc. until baby stops nursing.
B. Signaling Pathway: Suckling by baby stimulates nerve endings in nipple ---> nerve signal to HT --> release of oxytocin from post. pit. --> contraction of myoepithelial cells (similar to smooth muscle) surrounding alveolus (milk producing section of mammary gland) ---> milk ejection from lumen of alveolus ---> etc.
At same time, HT neurons stimulate ant. pit to release prolactin (PL) ---> stimulates inner layer of cells surrounding lumen of alveolus --> promotes milk production and secretion of milk into lumen of gland.
Question to think about: what's the circuit look like here? What's the IC? The effector? Etc.
Try problems 7-14 & 7-18.
To look at a more complex case using nerves & hormones helps to look at basic organization of nervous system first. This section is FYI -- not covered in class -- will be discussed after nerve cell function.
IV. How is Nervous System organized overall?
A. CNS & PNS.
1. CNS = brain + spinal cord
2. PNS -- Part of nervous system outside of CNS. See Purves 46.1 (46.2) -- Names of Divisons
a. Two divisions of PNS: Afferent (carrying info into the CNS) vs Efferent (carrying info away from the CNS)
b. Two divisions of Efferent: Somatic (controls skeletal muscle = voluntary actions) vs autonomic (controls all unconscious responses = automatic actions)
c. Two divisions of autonomic: Parasympathetic (PS) vs Sympathetic (S)
B. How do PS and S co-operate? (See Purves 46.10 (46.11)
1. What do they innervate (what organs to they connect to)?
a. Many organs innervated by both
b. Some organs innervated by only one
(1). liver, sweat glands -- S only
(2). tears -- PS only
2. What results does stimulation (signal from nerve) produce?
a. Not always S excites; PS inhibits. Ex: salivation -- S inhibits; PS excites
b. Usually S --> response needed in a crisis; PS --> response needed to return to relaxed state.
(1). Effects of S -- heart rate increases; liver releases glucose; bladder relaxes (to hold more).
(2). Effects of PS -- heart rate decreases, digestion & salivation increase.
V. Stress response -- How do hormones and nerves act together to respond to stress? See handout 16B.
A. Phase one -- Nerve (Sympathetic) activity stimulates target organs (that are not glands) --> Direct response of heart, liver, lungs, etc.
B. Phase two -- Nerve (Sympathetic activity) --> activation of glands
1. Stimulate pancreas ---> glucagon increases; insulin decreases --> additional stimulation of some target organs
2. Stimulate adrenal medulla --> release of epinephrine --> stimulation of same targets as sympathetic nerve activity & some additional targets -- hormones can reach where nerves can't go.
C. Phase three
-- stimulate HT/AP axis to produce cortisol
HT in brain ---> releases CRH --> AP ---> releases ACTH --> adrenal cortex ---> produces cortisol --> target organs ---> stimulation of breakdown of fats & protein for energy (sparing glucose for brain); inhibition of immune system.
Note that each additional phase is slower but involves additional degrees of amplification due to second messengers, transcription, etc.
Next Week: How do nerves carry signals?