C2006/F2402 '11 Outline for Lecture 19 --  (c) 2011 D. Mowshowitz  -- Lecture updated 04/05/11. (Minor corrections made; see Note on refractory periods.)

Handouts: Extra copies of paper handouts are in boxes outside Dr. M's office; 7th floor Mudd.

    19A: Diagrams for summation, & sensors.
    19B. How the same hormone (epinephrine) has different effects on different tissues.

Reminder: See Web-sites page for animations, relevant Nobel Prizes, and other interesting supplementary materials.

Note on refractory periods: There is some disagreement between authorities on the timing of the refractory periods. According to  Dr. Firestein, Becker, and most texts, 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, and 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).

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 fig. 45.13 (44.130 or Becker fig. 13-19. Some of this is review, but is included for clarity.

    A. Presynaptic Side -- Transmitters  -- See Sadava Table 44.1 (8th ed.) & 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 of NT

        (1). Role of AP: Action potential (AP) stimulates Ca⁺⁺ channel opening in plasma membrane, raising intracellular Ca⁺⁺

    Note that Ca⁺⁺ is the same as Ca²⁺. Chemists tend to use Ca²⁺ and biologists tend to use Ca⁺⁺.

        (2). Role of Ca⁺⁺: High intracellular Ca⁺⁺ promotes  release of transmitter (& exocytosis in general).

c. General Case --  how is exoctyosis of secretory vesicles triggered by high Ca⁺⁺?

        (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.

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. 45.14 (44.14)

(3). Reuptake by transporters (secondary active transport) -- NE, serotonin removed from cleft by reuptake.

• Endocytosis recovers membrane.

• Transporters recover transmitters.

    B. Post Synaptic Side -- PSP's = post synaptic potentials = small change in potential due to release of transmitter

1. NT can be inhibitory (NT generates an IPSP) or excitatory (NT generates an EPSP)

a. Inhibitory -- causes hyperpolarization (or stabilizes existing negative polarization) -- IPSP -- due to opening of K⁺ or Cl^- channels. Either K⁺ goes out or Cl^- comes in.

b. Excitatory -- causes depolarization -- EPSP -- 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.

• Faster response.

• 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 fig. 45.16 (44.17) or Becker 13-21 (13-23). Also see many pictures in both books of neuromuscular junction, or handout 18.

(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 fig. 7.19 (15. 17 or 44.16 ).

(4) Agonists and antagonists

(a). Uses -- both are common tools to study receptors for signal molecules, both NTs and hormones.

(b). Definitions:

• Agonists

  Mechanism:  Bind to receptor & cause same change in receptor conformation as the normal signal molecule.

  Result: Mimic signal molecule and cause same effect as normal ligand.
   

• Antagonists

  Mechanism: Bind to receptor, blocking binding of normal signal molecule, but do not cause usual conformational change. Do not activate receptor.

  Result: Block usual effect of ligand.

(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

*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. This problem as written does not refer to a standard synapse between two nerves.  However, suppose you are looking at a standard synapse between two nerves that uses AcCh as a transmitter. What effects will each of the treatments listed (1-5) have on transmission at a standard synapse? (Note -- The answers in the back of the book are correct for a standard synapse 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 19A , bottom, or Sadava fig. fig. 45.15 (44.15) or Becker 13-22 (13-24).

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 19A, 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.

    B. Receptor Proteins

    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 fig. 46.2 (45.2) & Handout 19A.) 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 fig. 46.5 (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 19B.

Try problem 6-11.

  D. Example of Using Different Second Messengers (& Different Receptors). See handout 19B.

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 are either agonists or antagonists of signaling molecules such as hormones, transmitters, etc.

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). See also handout 19B.

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 handout for next time.
** Not all alpha receptors use IP3.