Chapter 14. Signal Transduction Signal transduction is the process by which an extracellular signal alters intracellular events. 1. First and second messengers. 1) First messengers: refer to the extracellular signaling molecules, including neurotransmitters, hormones, and local mediators.

A) Neurotransmitters (synaptic signal): secreted by neurons and diffuse to target cells causing physiological response such as muscle contraction.

B) Hormones (endocrine signal): secreted by endocrine glands in trace amounts and transported by the bloodstream to target cells, causing physiological effects.

C) Local mediators: include growth factors and cytokines. They can be subdivided into autocrine and paracrine groups.  Autocrine group: extracellular signaling molecules secreted by autocrine cells act on the cells which released the substance.  Paracrine group: extracellular signaling molecules secreted by paracrine cells diffuse to and act on nearby cells.

2) Second messengers: refer to those molecules that mediate the action of the first messengers, such as cAMP, cGMP, Ca 2+, inositol triphosphate (IP 3 ), diacylglycerol (DAG).  One of the main functions of second messengers is to activate their cognate protein kinases. For instance, cAMP activates protein kinase A, cGMP activates protein kinase G, DAG activates protein kinase C, and Ca 2+ activates Ca 2+ / calmodulin protein kinases I, II, and III.

3) Receptors: are those molecules that are recognized and bound by first messengers. Receptors may be on the cell membrane or inside the cytosol. e.g. epinephrine binds to its receptor on the cell membrane causing activation of adenylate cyclase.

2. Mechanisms by which cAMP mediates the action of hormones. 1)The receptors: are membrane proteins with a hormone-binding domain on the extracellular side, and a loop on the cytosolic side which participates in the activation of stimulatory G protein (Gs). e.g. the  -adrenergic receptor is a 64 kDa protein that spans the target cell membrane.

The  -adrenergic receptor

Hormones that use cAMP as a second messenger CalcitoninCorticotropin Chorionic gonadotropinEpinephrine Follicle stimulating hormoneGlucagon Luteinizing hormoneLipotropin Thyroid stimulating hormoneParathyroid hormone NorepinephrineVasopressin Melanocyte stimulating hormone

2) G proteins: are the guanyl nucleotide- binding proteins which hydrolyze GTP.  The G protein that controls adenylate cyclase is called “stimulatory G protein ”, or Gs.  Gs consists of three subunits: , , and . G  -GTP is the active form while G  - GDP is the inactive form. These two forms can change to each other triggered by exchange between GTP and GDP on the  - subunit.

Active-inactive interconversion of Gs

 Activation of adenylate cyclase mediated by Gs: Hormone binds to the receptor activation of Gs (G  -GTP) G  -GTP diffuses and binds to adenylate cyclase activation of adenylate cyclase ATP is converted into cAMP.  After adenylate cyclase has been activated, G  -GTP is converted into G  -GDP, which then diffuses from adenylate cyclase and binds to G . The receptor is deactivated by phosphorylation

Activation of adenylate cyclase

 cAMP stimulates phosphorylation of target proteins: Most effects of cAMP are mediated by protein kinase A (PKA):

 Activated PKA phosphorylates many target proteins to alter their activity, such as that in glycogen metabolism:

3. Mechanisms by which inositol triphosphate (IP 3 ) opens Ca 2+ channels.

 Hormone (e.g. vasopressin) binds to a cell- surface receptor activation of phospholipase C (PLC) production of IP 3 and DAG.  IP 3 binds to the membrane of intracellular Ca 2+ stores (ER, sarcoplasmic reticulum in smooth muscle cell) opening of Ca 2+ channels cytosolic [Ca 2+ ] .

DAG PKC 被激活 DAG PKC PKC activation Hormone

 Cytosolic [Ca 2+ ]  responses in the target cell, such as smooth muscle contraction, glycogen breakdown, and vesicle release.  DAG is also a second messenger, it activates protein kinase C (PKC) by increasing the affinity of PKC for Ca 2+ phosphorylation of target proteins.

4. Mechanisms by which growth factors (GF) induce cell growth and differentiation. 1)Tyrosine kinase receptor: a membrane- spanning protein with an extracellular domain that is recognized and bound by GF, and a cytosolic domain with kinase activity. 2) Classes of tyrosine kinase receptors: type 1, 2, 3, 4 (such as epidermal GF receptor, insulin receptor, and platelet-derived GF receptor, and fibroblast GF receptor, respectively).

Classes of tyrosine kinase receptors

3) Binding of growth factor to tyrosine kinase receptor causes phosphorylation of target proteins in the cell. The phosphorylated target protein in turn activates the genes through a series of reactions, leading to expression of the specific gene. e.g. binding of EGF to EGF-R dimerization and autophosphorylation phosphorylation of target proteins response of the target cell (e.g. gene expression).

Mechanism of EGF receptor activation

5. Mechanisms by which steroid hormones regulate expression of specific genes  Steroid hormones are lipophylic molecules that can enter into the target cells by diffusion.  Receptors of steroid hormones are located in the cytosol or nucleus  The hormone-receptor complex undergoes some changes in size, conformation, and surface charge.

 The hormone-receptor complex then binds to a specific region of DNA (called the hormone response element, HRE) and activates or inactivates the specific genes.  Thyroid and retinoid hormones act by mechanisms similar to that of steroids.

6. Characteristics of receptor-mediated signal transduction A)High specificity B)High affinity C)Saturable D)Reversable E)High efficiency