How can one signal molecule (hormone, transmitter, etc.) produce different effects on different tissues?
A . Two Basic Methods
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.
2. The solution: 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.
a. In skeletal muscle, PKA phosphorylates phosphorylase kinase, glycogen phosphorylase etc, as on handout 12D.
b, In smooth muscle surrounding the bronchioles, PKA phosphorylates a protein (MLCK) needed for contraction, inactivating it. Therefore contraction cannot occur.
FYI only: For smooth muscle to contract, an active kinase (MLCK) must bind Ca++ (in the form of a calmodulin /Ca++ complex). If MLCK is phosphorlyated, the Ca++/calmodulin complex cannot bind to it, and contraction does not occur. (We will discuss the role of calmodulin and the mechanism of smooth muscle contraction later.) If you like to see all the details of the role of MLCK, see Becker fig. 16-24.
2. Using different receptors & second messengers in different cell types
(See Becker fig. 14-23 (10-24). 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.
B. Example of Using Different Second Messengers (& Different Receptors)
→ Ca++ released from ER → intracellular Ca++ up → stimulates contraction.
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. Epinephrine binds to receptors on some smooth muscles (ex: around arterioles)
c. 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 at end of lecture 15 for details of receptor properties.)
c. Two types of receptors activate different G proteins and generate different second messengers as on handout 12A. (We will go over the details later. What you need to know so far is below.)
(1). Beta receptors → G protein type (Gs)→ cAMP response → PKA
(2). Alpha1 receptors → different G protein (Gp) → 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 6-20 & 6-21. Note that you do not need to know the details of how IP3 is generated, but you do need to know that PLC is the enzyme responsible for producing IP3. For unknown reasons, the Greek symbols in these problems did not print in the latest edition of the problem book, and there are spaces instead. Where it says ' 1' or ' 2' receptors it should say 'α1' or 'α2' receptors. Where it says ' / ' it should say 'β/δ'. (There is a missing β & δ in the description of experiment (4) in the table, and in the sentence after the end of 6-21, part C-3.)
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 on handout 12A. We will go over this later.