C2006/F2402 '10 Outline for Lecture 17 -- (c) 2010 D. Mowshowitz -- Lecture updated 03/31/10.
Handouts: 17A, B & C. Not on line. Extra copies of class handouts are in boxes outside Dr. M's office; 7th floor Mudd.
17A: Diagrams for summation,
17B. How the same hormone (epinephrine) has different effects on different tissues.
17C. IP3/Ca++ as second messengers.
Note on refractory periods: There is some disagreement between authorities on the timing of the refractory periods. According to handout 16A, and to Becker, the absolute refractory period comes right after the spike of the action potential. According to some, the absolute refractory period coincides more or less with the spike; the relative refractory period follows after the spike. All agree about the underlying mechanism. The absolute refractory period corresponds to the time when the Na+ channels are inactivated (so depolarization is not possible). The relative refractory period corresponds to the time when the Na+ channels can be activated, but the voltage gated K+ channels are still open (so depolarization to threshold requires a larger stimulus).
Reminder: See Web-sites page for animations, relevant Nobel Prizes, and other interesting supplementary materials.
I. Nerve-Nerve Synapses, cont. -- What determines if a nerve impulse will be passed on to the next neuron? For nice overall pictures see Sadava 44.13 or Becker fig. 13-19. Some of this is review, but is included for clarity.
A. Presynaptic Side -- Transmitters -- See Sadava Table 44.1 & Becker fig. 13-18 (13-20).
1. One major type of transmitter (NT) per synapse (released from pre-synaptic side)
a. In CNS, many diff. transmitters. Usually amino acids or their derivatives. Major ones are glutamate (excitatory) & GABA (inhibitory).
b. In PNS usually norepinephrine (NE) or acetyl choline (AcCh).
2. One transmitter per Neuron. Usually only one major transmitter released by any neuron. Therefore one major transmitter released -- the same one -- at all synapses made by that neuron.
3. Release of Transmitter:
a. Location of Transmitter: Neurotransmitters are in vesicles (except for gaseous NTs)
b. Trigger for release: Action potential (AP) stimulates Ca++ channel opening in plasma membrane, raising intracellular Ca++
c. Exocytosis: High intracellular Ca++ promotes release of transmitter.
d. General Case: High intracellular Ca++ promotes exocytosis in general.
(1). Source of Calcium: Ca++ can come from outside the cell or be released from ER.
(2). How Calcium enters cytoplasm: Channels open -- in plasma membrane or ER membrane.
(3). Which channels open: depends on signal. Signal can be NT, hormone, etc.
4. Effects of transmitter (on target) can vary. Some transmitters are always excitatory or inhibitory; other transmitters vary in effect -- depends on what types of receptors are present for that transmitter (on the post-synaptic side).
a. In nerve-nerve transmission -- most NTs always have the same effect, an EPSP or IPSP, but some NTs can produce EPSPs or IPSPs depending on the receptor(s) present.
b. When a signal molecule (NT or hormone) contacts a target tissue (muscle or gland) -- the effects on the target may be inhibitory or excitatory -- depending on the receptor(s) present. Some examples are below and on handout 17B.
5. Getting rid of transmitters -- How to turn off the signal?
a. Transmitter doesn't remain in synaptic cleft for long.
b. Different methods for getting rid of dif. transmitters
(1). Diffusion away from cleft -- most NT are small molecules.
(2). Destruction by enzymes in cleft. For ex, acetyl choline esterase (AcChE) in cleft breaks up AcCh (Choline is reused). See Sadava fig.44.14
(3). Reuptake by transporters (secondary active transport) -- NE, serotonin removed from cleft by reuptake. (Endocytosis recovers membrane; transporters recover transmitters.)
→ more stimulation of target nerves. (Probably has other effects as well.)
c. Many drugs affect release/fate of transmitters; for ex.
(1). Prozac prevents serotonin reuptake -- transmitter stays around longer
(2). Malathion (insecticide) & nerve gas block AcChEsterase → continuous stimulation of muscle target cells→ spasms
B. Post Synaptic Side -- PSP's = post synaptic potentials = small change in potential due to release of transmitter
1. Can be inhibitory (NT generates an IPSP) or excitatory (NT generates an EPSP)
a. Inhibitory -- causes hyperpolarization (or stabilizes existing negative polarization) due to opening of K+ or Cl- channels. Either K+ goes out or Cl- comes in.
b. Excitatory -- causes depolarization due to opening of cation channels. Allows movement of both Na+ & K+. Why does this depolarize, or why is Na+ in>> K+ out?
c. Terminology -- a single IPSP or EPSP usually refers to the small change in potential due to release of transmitter caused by a single AP. The total PSP depends on the algebraic sum of multiple IPSP's and EPSP's as explained below.
2. Any given synapse is excitatory or inhibitory -- What determines it?
a. Receptor is crucial (See table below)
(1). One type of receptor for neurotransmitter at each synapse.
(2). Receptor determines what happens at the synapse -- if target is excited or inhibited.
(3). Receptor can be direct or indirect
(a) ionotropic (direct) -- receptor is itself an ion channel.
Ligand binding always opens channel.
Not always excitatory -- depends on type of channel opened.
Example -- the nicotinic AcCh receptor (see table below)
For pictures see Sadava 44.17 or Becker 13-21 (13-23). Also see many pictures in both books of neuromuscular junction, or handout 14.
(b) metabotropic (indirect) -- receptor uses GPCR & 2nd messenger.
Response is slower.
Effects can be more varied & more extensive.
Can be used to open or close ion channels.
Example: the muscarinic AcCh receptor & all adrenergic receptors (see table)
For picture see Sadava 44.16.
(4) Agonists and antagonists
(a). Uses -- both are common tools to study receptors for both NTs and hormones.
Agonists -- bind to receptor & cause same change in receptor conformation as the normal signal molecule. (Therefore, cause same effect.)
Antagonists -- bind to receptor, blocking binding of normal signal, but do not cause usual conformational change. (Therefore, block usual effect.)
(c). Terminology: Some receptors named by their common ligand and most common agonist or antagonist. For example, the nicotinic acetyl choline receptor. Ac Ch = NT; nicotine = agonist.
b. Overall: One major receptor/neurotransmitter pair per synapse.
3. Major Types of Receptors in the PNS -- Reference & summary
Basic Type of Receptor
Detailed Type of Receptor
Direct (It's a Na+/K+ channel)
Contract skeletal muscle
Indirect; 2nd messenger & effect varies
Toxin from Amanita muscara (muscarine)
Slow heart beat
Epinephrine (adrenalin) & NE; NE> E
Indirect; 2nd messenger & effect varies
Contract smooth muscle
Epi. & NE; E> NE
Indirect; cAMP is 2nd messenger
Relax smooth muscle (bronchodilates); increase heart beat
*Both alpha and beta have subtypes that differ in location, mechanism & effect; same receptors used for epinephrine acting as a hormone or neurotransmitter.
** This is the receptor at the neuromuscular junction. See Becker fig. 13-21 (13-23). This is the AcCh receptor people mean when they talk about "THE" acetyl choline receptor.
Look at problem 8-16, part C. Assume you are looking at a standard synapse between two nerves that uses AcCh as a transmitter. What are the answers to parts 1-5? What effects will you expect on transmission at a standard synapse? (Note -- this problem as written does not refer to a standard synapse between two nerves. However the answers in the back of the book are still okay except for part 4. What is the right answer to part 4 for a standard synapse?)
4. Features of Total PSP's (To compare to AP's)
a. Total PSP's are graded -- size is proportional to stimulus (as with receptor potentials, see below). Size is not all or none. (Unlike action potentials.)
b. PSP's are local -- die out if don't reach threshold. (Not regenerated like AP's.)
c. PSP's are caused by opening/closing of ligand gated channels. (What kind of channel is needed for AP's?)
To review IPSP's and EPSP's try problem 8-10.
C. Post Synaptic Side -- Summation -- See Handout 17A , bottom, or Sadava fig. 44.15 or Becker 13-22 (13-24).
→ AP. See handout 17A, bottom (cases a-d)
1. Inputs (IPSP's & EPSP's) to cell body/dendrites are summed -- changes spread around cell body to initial segment (or die out).
2. No AP in cell body. No voltage gated channels in cell body so no AP generated there
3. Axon Hillock. Voltage gated channels begin at initial segment (also called the "trigger zone" or axon hillock) so AP starts there. See Becker fig. 13-11 (13-14) or Sadava 44.15.
4. Inputs summed over space and/or time -- need to depolarize past threshold at axon hillock to
a. No summation achieved
b. Temporal summation: Multiple EPSP's delivered close enough together in time can add up → AP
c & d. Spatial summation:
Case c: Multiple EPSP's delivered at different spots can add up → AP
Case d: EPSP + IPSP cancel each other out
e. Why you need summation:
(1). A single EPSP is not enough to → AP
(2). IPSP's & EPSP's are summed: net effect depends on both inhibitory and excitatory input. Remember there are about 1000 synapses (inputs) on body & dendrites of average neuron. See Becker fig. 13-22 (13-24). (See circuits next time for how you use this.)
Review Problem 8-8, parts A to H, and recitation problem 8-2.
So far: Have explained how nerve signal is transmitted down an axon and on to the next nerve. How does signal get started? How does it have an effect? These Qs are addressed in the next two sections.
II. Sensors -- How a nerve signal gets started. See handout 17A, top. Sadava has a whole chapter on Sensory Systems. (Chapter # depends on which edition of the text you have.) Only a few general principles discussed here. See Sadava for examples & details.
A. The Problem: How does a small stimulus (from the internal or external environment) reach the nervous system?
1. The Question: Where does input come from, if not from another neuron? How do you get input from the environment -- from sight, sound, etc. -- and send it to the CNS?
2. The Short Ans:
Touch, hearing, etc., produce a small response = change in polarization by opening/closing channels in special cells (receptor cells or sensors).
Change in opening of channels (& therefore change in polarization) is proportional to stimulus.
If the small change in polarization is big enough (over threshold) -- it opens voltage gated channels which generates a big response -- an AP. (The 'big bang' or the 'toilet flush,' so to speak.) See left-most case on the 'big bang' handout.
B. Receptor Proteins
1. Special (Sensory) cells contain receptor proteins for stimuli (pressure, light, heat, chemicals, etc.).
2. How do protein receptors detect stimuli?
a. Stimuli → Change in conformation of receptor → open or close channels in membrane → change in polarization of membrane.
b. How are channels opened or closed? See Sadava 45.1.
(1) Directly -- receptor is part of a channel = an ionotropic receptor. Examples: receptors for mechanical stimuli (touch, hearing, balance), & temperature (heat/cold). Receptor changes shape and channel opens.
(2) Indirectly -- receptor is not part of a channel = a metabotropic receptor. Change in conformation of receptor activates a G protein. G protein or 2nd messenger opens/closes channel. Examples: receptors for chemicals (taste, smell, etc.), electromagnetic radiation (vision).
C. Receptor Potentials
1. Response to stimulus is graded. Stimulus → local graded response. The more stimulus, the more channels open (or close), and the bigger the graded potential (bigger depolarization or bigger hyperpolarization) in the sensory/receptor cell.
2. Terminology -- graded response in receptor/sensory cell is called a generator potential or receptor potential.
D. Receptor or Sensory Cells. Special cells with receptor proteins for detecting stimuli
1. Modified neuron -- sensory cell is a modified neuron capable of generating AP itself. (See Sadava 45.2 & Handout 17A.) Examples: sensory cells for detecting stretch or smell.
2. Cell that cannot generate an AP itself .
a. How get an AP? Sensory cell releases transmitter and triggers AP in next cell (a neuron). See Sadava 45.5 & handout. Examples: sensory cells for detecting light, taste, sound and balance.
b. Type of cell. This type of sensory cell can be a modified neuron or epithelial cell.
Question to ask yourself: What type of channels does a cell need in order to generate an AP? If you are curious about the details of how the AP is generated, see notes of '08.
E. All stimuli (whatever the modality) give same message to CNS (= AP's). If AP is all or nothing, how do you know which stimulus it was? And how much?
1. Number, frequency of AP's indicate length (duration) and strength (intensity) of stimulus.
2. Wiring (what part of brain is stimulated) = labeled lines = indicates location of stimulus and type (modality) of stimulus -- taste, stretch, etc. If you get a punch in the eye, you set off light receptors. For a less violent example, take a very sharp pencil and tap your upper lip. What sensors did you trip off? (For contrast, tap your arm.)
III. How does a nerve signal produce an effect?
A. General solution -- nerve signal triggers an effect in a target tissue (an effector) -- muscle contracts, gland secretes, etc. Some examples of how this works next time.
B. The Problem -- One signal molecule (hormone, transmitter, etc.) can produce different effects on different target tissues such as different smooth muscles or skeletal muscle vs. smooth muscle.
C. Two Basic Methods -- See Handout 17B.
1. Using the Same Receptor & same 2nd messenger, but different Target Proteins
a. An example:
(1). In skeletal muscle: epinephrine causes glycogen breakdown.
(2). In smooth muscle of lung: epinephrine causes muscle relaxation.
b. Why does this make sense?
(1). Epinephrine (also called adrenaline) is produced in response to stress.
(2). In response to stress, need to "mobilize" glucose -- release it from storage so it can be broken down to provide energy. Therefore need to increase glycogen breakdown (and decrease glycogen synthesis) in muscle (& liver).
(3). In response to stress, need to breathe more deeply. Therefore need smooth muscle around tubes that carry air (bronchioles) to relax.
c. How is this possible? Same receptors, same 2nd messenger (cAMP) are used.
d. The solution: Different target proteins. PKA is activated in both skeletal and smooth muscle. However the target proteins available to be phosphorylated are different in the two tissues. Therefore different proteins are phosphorylated and activated (or inactivated) in the two different tissue types.
(1). In skeletal muscle -- PKA phosphorylates (& activates) the enzyme phosphorylase kinase, which in turn phosphorylates (& activates) the enzyme that breaks down glycogen to release glucose. See texts for more details. (Becker, fig. 14-25 or Sadava 15.18)
(2).In smooth muscle surrounding the bronchioles -- PKA phosphorylates a protein (MLCK) needed for contraction, inactivating it. Therefore contraction cannot occur.
2. Using different receptors & second messengers in different cell types
(See Becker fig. 14-24 (14-23). An example -- effects of epinephrine (adrenaline) on smooth muscle. Some smooth muscles relax, and some contract in response to epinephrine. In this case, different receptors & 2nd messengers are involved. How does this work? See below.
Try problem 6-11.
C. Example of Using Different Second Messengers (& Different Receptors). See handout 17B.
1. The phenomenon:
a. Epinephrine (secreted in response to stress) has different effects on different smooth muscles:
(1). On some smooth muscles, epi → contraction
(2). On other smooth muscles, epi → relaxation (as above)
b. How does this make sense?
(1). In peripheral circulation -- smooth muscles around blood vessels (arterioles) contract, diverting blood from peripheral circulation to essential internal organs
(2). In lungs -- smooth muscles around tubes carrying air (bronchioles) relax, so lungs can expand more and you can breathe more deeply.
2. How Ca++ fits in:
a. Ca++ stimulates muscle contraction.
b. To give contraction: Epinephrine binds to receptors on some smooth muscles (ex: around arterioles) → Ca++ released from ER → intracellular Ca++ up → stimulates contraction.
c. To give relaxation: Epinephrine binds to receptors on some smooth muscles (ex: around bronchioles) → phosphorylates protein needed for response to Ca++, preventing response.
3. Role of receptors
a. Two basic types of epinephrine receptors -- called alpha and beta adrenergic receptors (adrenergic = for adrenaline). The two types are distinguished (primarily) by their relative affinities for epinephrine (adrenaline) and norepinephrine (noradrenaline).
b. Some types of smooth muscle have mostly one type of receptors; some the other. (See table below and table above for details of receptor properties.)
c. Two types of receptors activate different G proteins and generate different second messengers. (Details on handout 17C.)
(1). Beta receptors → G protein of one type (Gs)→ activates enzyme (Adenyl cyclase) → second messenger (cAMP) → PKA
(2). Alpha 1 receptors → different G protein (Gp) → activate different enzyme (phospholipase C or PLC) → different second messenger (IP3) → binds to receptors on ER membrane → opens Ca++channels in ER → Ca++ release from ER → contraction
4. How does this all work to allow appropriate response to stress (epinephrine)?
a. Beta type receptors. Beta receptors are found in lung tissue in smooth muscle surrounding bronchioles.
Stress (pop quiz, lion in street, etc.)→ epinephrine → muscles relax → bronchioles dilate → deeper breathing → more oxygen → energy to cope with stress.
b. Alpha type receptors. Alpha receptors are found in smooth muscle surrounding blood vessels of peripheral circulation.
Stress → epinephrine → muscles contract → constrict peripheral circulation → direct blood to essential organs for responding to stress (heart, lungs, skeletal muscle).
To review effects of different receptors, try problems 6-21 & 6-22. Note that you do not need to know the details of how IP3 is generated. If you are curious, see Becker fig. 14-10 or class handout.
5. Medical Uses of all this.
Epinephrine can be used during an asthmatic attack to relax bronchi and ease breathing. Overuse of this type of broncho-dilator eases breathing temporarily but masks underlying problem (inflammation of lung tissue) and can have additional serious long term effects (from overstimulation of heart which also has beta receptors). Heart and lungs have slightly different types of beta receptors, so drugs (agonists) have been developed that stimulate one and not the other (unlike epinephrine). Many drugs either imitate or block the effects of signaling molecules such as hormones, transmitters, etc.
- Agonist = mimic of hormone or ligand; binds to receptor and has same effect as ligand.
- Antagonist = blocker of effect of hormone or ligand; binds to receptor (and prevents binding of normal ligand) but does not activate the receptor.
Try Problem 6-8 & 6-9 if not yet. (To review agonists & antagonists.)
6. Summary of epinephrine effects on smooth muscle (in lung vs peripheral circulation)
Effects of Epinephrine on Smooth Muscle
|Receptor Type||Alpha1 adrenergic**||Beta adrenergic|
|Receptor binds||norepinephrine> epinephrine||epinephrine ≥ norepinephrine|
|G protein activates||PLC (phospholipase C)*||adenyl cyclase|
|Effect of 2nd messenger||Ion channel in ER opened||PKA activated → Ca++ response blocked|
|Effect on Ca++||Ca++ released into cyto.||None (in bronchioles)|
|Effect on smooth muscle||Contraction||Relaxation|
|Tissue involved||Peripheral Circulation (arterioles)||Lungs (bronchioles)|
|Final Effect||Blood directed to central organs||Breathing easier|
Note: There are more than two types of epinephrine receptors on smooth muscle cells, so epinephrine may affect smooth muscle in other tissues in other ways. (There are subtypes of alpha and subtypes of beta.)
* Details of how PLC generates IP3 are in texts and on class handout
** Not all alpha receptors use IP3.
Next time: Wrap up of IP3 pathway; How are circuits organized, and how do nerves and muscles work to give contractions?