C2006/F2402 '11 -- Outline for Lecture 20 --  (c) 2011 D. Mowshowitz  -- Lecture updated 04/07/11

Handouts:  20A -- IP3 Signaling

20B  circuits & setup of nervous system  
20C PNS  & Muscle structure (see texts or web for muscle cell structures).

I. 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.

1.  Using the Same Receptor & same 2nd messenger, but different Target Proteins

An example: effects of epinephrine on skeletal muscle (glycogen breakdown) vs smooth muscle of lung (relaxation).

        2. Using different receptors & second messengers in different cell types 

 An example -- effects of epinephrine (adrenaline) on different smooth muscles. (See Becker fig. 14-24 (14-23). 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 handout 19B & last lecture for details.

II. Signaling with Lipids (PI Derivatives)
-- Handout 20A

    A. Many inositol derivatives are involved in signaling -- this is a current hot subject of investigation.

1. What is PI? Phosphatidyl inositol (PI) is a membrane lipid; inositol part faces cytoplasm.

2. Role of Kinases

a. Kinases add additional phosphates to hydroxyls on PI.

b. Many different products are possible, as PI has 5 free hydroxyls. Examples:

  • PIP2 or PI 4,5 bisphosphate-- has phosphate added to 4 & 5 positions.
  • PIP3  -- has phosphates on 3, 4, & 5 positions.

c. Regulation:  Activation of kinases (to add phosphates) and phosphatases (to remove the added phosphates) is regulated by hormones, growth factors, etc.

3. What does phosphorylated PI do?

a. Generates second messengers: Phosphorylated PI (for example, PIP2) can be split to generate second messengers, such as IP3 and DAG. The second messengers bind to and activate enzymes.

b. Recruitment: Phosphorylated PI (for example, PIP3) can recruit some enzymes to the membrane; binding to the modified PI  activates the enzymes (no second messengers).

   B. Details for DAG/IP3/Ca++ pathway. See handout 17C & Becker figs. 14-9 & 14-10 or Sadava fig. 7.15 (15.13).

1. How IP3 and DAG are generated

a. Activated G protein binds to phospholipase C (PLC)

b. PLC cleaves PIP2 in membrane → two parts. For structures see handout 15B and Becker fig. 14-9.

(1). PIP3  -- soluble, in cytoplasm; also known as InsP3

(2). DAG = diacyl glycerol = glycerol with two fatty acids. DAG remains in membrane.

2.  Role of IP3/Ca++

a. IP3 opens Ca++ channels in the ER, raising Ca++ in cytoplasm. (Becker fig. 14-11 for IP3 effect; fig 14-12 for overall Ca++ regulation.)

b. Ca++ acts alone or as complex with calmodulin (a protein) -- complex (calmodulin-Ca++) or Ca++ alone binds to and alters activity of many proteins. See Becker fig. 14-14 (14-13) for pictures of calmodulin.

c.  Ca++ affects many processes -- sometimes called "3rd messenger." For example, changes in [Ca++]

  • can trigger exocytosis (& secretion)
  • can trigger muscle contraction
  • are involved in egg fertilization (see Becker fig.14-13 (14-14) or Sadava  fig. 7.16 (15.14) for some nice pictures). 

3. Role of DAG

a. DAG (in membrane) activates protein kinase C (= PKC, not to be confused with PLC).

b. What is PKC? "PKC" is a family of related enzymes involved in many different processes -- act by phosphorylating other proteins. If you are interested, see Becker or advanced texts for details. Some PKC's require Ca++.  PKC and PKA have different target proteins.

Try problems 6-5, 6-10 & 6-16.

III. How Nervous System is Organized

    A. Simple circuits  -- see handout 20B, bottom or Sadava fig. 47.3 (46.3)

1. One synapse, 2 neurons -- monosynaptic circuit -- how sensory neuron signals an effector.

2. Circuit with multiple synapses -- how antagonistic muscles are controlled. For example, when stretch is detected in a muscle, that muscle contracts and the antagonistic muscle relaxes.

a. Signal to skeletal muscle is always +; a signal (+) means contract; no signal means relax.

b. Signal to neuron (than controls muscle) can be excitatory or inhibitory.

c. What makes the (antagonistic) skeletal muscle relax?

  • Relaxation occurs because the antagonistic muscle gets no signal to contract.

  • The muscle does not get an inhibitory signal -- it just doesn't get an excitatory signal.

d. Who gets an inhibitory signal? The motor neuron that innervates (goes in to) the antagonistic muscle gets an inhibitory signal, not the muscle itself. The motor neuron is inhibited and does NOT fire an AP, so the muscle is not triggered to contract.

3. Role of brain -- adds up/down (as vs. in/out) component

4. FYI: Where is all this located? see Sadava fig. 47.3 (46.3); will not be discussed in class.

    B. How is NS organized overall? See handout 20B top, Becker 13-1 (6th ed. only) or Sadava fig. 47.1 (46.1).

1. CNS = brain + spinal cord

2. PNS -- Names of Divisons

a. Afferent vs Efferent.

(1) Afferent = carrying info into the CNS
(2) Efferent
= carrying info away from the CNS

b. Efferent subdivided into: Somatic vs autonomic

(1) Somatic = controls skeletal muscle
(2). Autonomic = controls everything else

c. Autonomic subdivided into: Parasympathetic (PS) vs Sympathetic (S)

Try problem 8-8, part I.

    C. How do PS and S co-operate? See Sadava fig. 47.10 (46.10).  What do they do?

1. What do they innervate?

a. Many organs innervated by both

b. Some organs innervated (stimulated) by only one

(1). sweat glands -- S only

(2). tears -- PS only

2. What results does stimulation produce?

a. Not always S excites; PS inhibits. Ex: salivation -- S inhibits; PS excites

b. Usually:

(1). S → response needed in a crisis

(2). PS → response needed in relaxed state. ("para makes you pause")

c. Examples:

(1). S heart rate up; liver releases glucose; bladder relaxes (to hold more);

(2). PS heart rate down, digestion, salivation up.

    D. General Set up of wiring of efferent PNS -- see handout 20C

1. First neuron -- same in Somatic and Autonomic

a. Location -- body in CNS

b. Neurotransmitter -- releases AcCh (Acetyl choline)

c. Receptor -- AcCh receptor (on effector/next neuron) is nicotinic (direct)

d. Effect -- effect of transmitter on next cell is always excitatory

2. Second neuron (post ganglionic) -- found in autonomic only

a. Location -- Body in ganglion (outside CNS).

b. Neurotransmitter

(1). Parasympathetic -- releases AcCh

(2). Sympathetic -- usually releases NE (norepinephrine)

c. Receptor (on effector) -- indirect (metabotropic)

(1). AcCh (cholinergic) receptor is muscarinic

(2). NE (adrenergic) receptor can be alpha or beta (see table in last lecture) -- 2nd messenger varies

(3). Effect of transmitter can be excitatory or inhibitory.

d. Adrenal medulla

        (1). Medulla ≡ ganglion -- but neurons have short axons. (Usual 'neuron #2' has long axon.)

        (2). Release neurotransmitter (mostly E = epinephrine) into blood from end of short axons (within medulla).

        (3). Role of E -- 'NT' goes into blood, so E acts as neuroendocrine instead of neurotransmitter.

Try problem 8-8 part J.

    E. Major receptors in the PNS -- Reference & summary -- See table in last lecture.

IV. Muscle Overview
  -- See handout 20C, bottom

    A. Common Features

1. Have actin (MF) and myosin

2. Actin and myosin slide past each other; neither shortens. (For skeletal muscle, see Becker fig. 16-16.)

3. Electrically excitable -- Stimulus usually generates an AP (in muscle membrane) which then triggers contraction; some smooth muscles respond w/o generating an AP.

4. Use Ca++ to stimulate contraction  --  Stimulus usually causes a rise in cytoplasmic Ca++ in muscle contraction. But details of where Ca++ comes from, what triggers its release, and how it acts, differ; see below & next time.

5. Use hydrolysis of ATP to power contraction.

6. Bridge Cycle.  All muscles achieve contraction (shortening of muscle) by a bridge cycle. Details of cycle differ.

    B. Three main types -- smooth, cardiac and skeletal (See handout 20C or Sadava Chap. 48 (fig 47.7) or Becker Chap. 16. Compare Becker figs. 16-10, 16-22 & 16-23.

The major features of smooth and skeletal muscle are outlined separately below, but actual lecture may skip back and forth. Details of cardiac muscle, skeletal muscle contraction, & anything on smooth muscle we don't get to, will be covered next time.

     C. Some Major Differences

1. Structure -- See handout 20C; more details next time

a. Cells Fused?

    (1). No -- Smooth muscle -- individual, unfused cells.

    (a). Single Unit smooth muscle -- the cells are connected by gap junctions and contract as a unit -- are electrically coupled.

    (b). Multi unit smooth muscle -- the cells are not coupled electrically; cells are stimulated and contract as multiple individual units.

    (2) Fused at ends -- cardiac

    (3) Fused, multinucleate  -- skeletal

b. Striated vs. not. How are actin/myosin fibrils arranged? Bundles or sarcomeres?

c. Structure of nerve/muscle synapse. Details for nerve-smooth muscle synapse next time; see handout 18, or text, for diagram of nerve-skeletal muscle synapse. 

2. What controls contraction?

a. Skeletal Muscle

(1). Innervated by somatic system

(2). Signal is always excitatory.

(3). Receptors: Neurotransmitters at nerve/muscle synapse use nicotinic receptors (direct -- ionotropic).

(4). Source of Ca++: Stimulus generates an AP in the muscle membrane, which causes release of Ca++ from ER. (ER called sarcoplasmic reticulum or SR in muscle.)

Important Note: Skeletal muscle does get hormonal stimulation (has receptors for hormones), but hormones do not affect contraction.

b. Smooth Muscle

(1). Innervated (not enervated) by autonomic neurons. See handouts. 

(2). Stimulus can be excitatory or inhibitory.

Examples in previous lectures: epinephrine can cause smooth muscle contraction (through IP3) or relaxation (through cAMP). Response depends on receptors on smooth muscle.

(3). Contraction influenced by hormones as well as autonomic neurotransmitters

(4). Stimulus doesn't always generate an AP in muscle membrane.

(5). Pacemakers? Pacemaker activity, not external stimulus, controls contraction in some smooth muscles. (See below; details of pacemakers next time.)

(6). Ca++ to trigger contraction comes from outside cell &/or ER.

(7). Has latch state; unlike striated muscle. Can remain contracted longer without input of ATP.

c. Cardiac Muscle -- Details next time.

(1). Contraction controlled by pacemaker cells. (Remember the Loewi experiment -- isolated hearts beat without any innervation.)

(2). What are pacemaker cells? Pacemaker cells fire APs simultaneously, and this stimulates the other cells, the contractile cells (that do not have pacemaker activity), to contract.

(3). Role of hormones & NTs: Neuronal and chemical signals can speed up or slow down pacemakers; mechanism next time.

At this point, it helps to start making a table that summarizes all the similarities and differences between the 3 types of muscle. Fill it in as you go -- add to it as you find out more about the structure and function of the different types.

V. Smooth muscle

    A. What use is smooth muscle? What unique properties does it have?

1. Location -- much of it makes up walls of hollow organs & tubes. Maintains shape and pushes contents along.

2. Contraction speed & rate of fatigue -- relatively slow for both.

3.  Latch state possible -- can remain contracted for prolonged period without further input of ATP.  (One ATP split per bridge cycle, but cycle is much slower than for skeletal.)

4. Length over which it contracts/stretches  -- relatively long.

5. Contracts/relaxes in response to many different stimuli -- nerves, hormones, stretch, etc.

Overall: Can integrate multiple signals and maintain "tone" over wide range of length with economical use of ATP.

     B. Details of Structure Next Time

Next time: How muscle contracts; intro to heart & circulation if time.