Vander's Human Physiology Chapter 5

receptor

specific target-cell proteins that intercellular chemical messengers (ligands) bind to

the binding of a messenger to a receptor changes the conformation, which activates it

ligand

chemical messenger

signal transduction

a sequence of events in the cell leading to the cell's response to that messenger that is initiated by the binding of a messenger to a receptor

The "signal" is the receptor activation, and "transduction" denotes the process by which a stimulus is transformed into a response

What is the nature of the receptors that bind intercellular chemical messengers?

proteins or glycoproteins located either in the cell's plasma membrane or inside the cell, either in the cytosol or the nucleus

In contrast, a much smaller number of lipid-soluble messengers diffuse through membranes to bind to their receptors located inside the cell.

plasma membrane receptors

transmembrane proteins - span the entire membrane thickness.

They have hydrophobic segments within the membrane, one or more hydrophilic segments extending out from the membrane into the extracellular fluid and the intracellular fluid

These are much more common because a lot of messengers are water-soluble and can't diffuse across the lipid-rich (hydrophobic) plasma membrane

intracellular receptors

located in membranes but exist in either the cytosol or the cell nucleus.

they have a segment that binds the messenger, other segments that act as regulatory sites, and a segment that binds to DNA

plasma membrane vs intracellular receptors

plasma membrane receptors can transduce signals without interacting with DNA, whereas all intracellular receptors transduce signals through interactions with genes

specificity

a given protein binds a particular ligand and not others if its binding site for that ligand is specific. Although a given chemical messenger may come into contact with many different cells, it influences certain cell types and not others. Cells differ in the types of receptors they possess

the neurotransmitter norepinephrine

causes muscle cells of the heart to contract faster but, via the same type of receptor, regulates certain aspects of behavior by acting on neurons in the brain. The receptor functions as a molecular switch that elicits the cell's response when "switched on" by the messenger binding to it.

a single type of receptor can be used to

produce different responses to the same chemical messenger in different cell types

saturation

The degree to which receptors are occupied by messengers. If all are occupied, the receptors are fully saturated; if half are occupied, the saturation is 50%, and so on.

affinity

The strength with which a chemical messenger binds to its receptor

Differences in affinity of receptors are important for therapeutic drugs in treating illness; receptors with high affinity for a ligand require much less of the ligand (that is, a lower dose) to become activated

competition

The ability of different molecules, generally with similar structure to the natural ligand, to compete with a ligand for binding to its receptor

antagonist

a molecule that competes with a ligand for binding to its receptor but does not activate signaling normally associated with the natural ligand. Therefore, an antagonist prevents the actions of the natural ligand. Certain types of antihistamines are examples of antagonists.

agonist

A chemical messenger that binds to a receptor and triggers the cell's response; often refers to a drug that mimics a normal messenger's action. Some decongestants are examples of agonists (phenylephrine and oxymetazoline)

down-regulation

A decrease in the total number of target-cell receptors for a given messenger; may occur in response to chronic high extracellular concentration of the messenger. It reduces the target cells' responsiveness to frequent or intense stimulation by a messenger, desensitizing them, making it a local negative feedback mechanism

internalization

during down-regulation, the messenger-receptor complex is taken into the cell by receptor-mediated endocytosis, increasing the rate of receptor degradation inside the cell and decreasing the number of plasma membrane receptors

up-regulation

An increase in the total number of target-cell receptors for a given messenger; may occur in response to a chronic low extracellular concentration of the messenger.

The greater the number of receptors available to bind a ligand

the greater the likelihood that such binding will occur

increased sensitivity

The increased responsiveness of a target cell to a given messenger; may result from up-regulation of receptors.

Ex. when the nerves to a muscle are damaged

the delivery of neurotransmitters from those nerves to the muscle is decreased or eliminated. With time, under these conditions, the muscle will contract in response to a much smaller amount of neurotransmitter than normal. This happens because the receptors for the neurotransmitter have been up-regulated, resulting in increased sensitivity

recruitment to the plasma membrane of intracellular vesicles

The vesicles fuse with the plasma membrane, thereby inserting their receptors into the plasma membrane. Receptor regulation in both directions (up- and down-regulation) is an excellent example of the general physiological principle of homeostasis, because it acts to return signal strength toward normal when the concentration of messenger molecules varies above or below normal.

receptor activation

the initial step leading to the cell's responses to the messenger

five cellular responses

changes in:

(1) the permeability, transport properties, or electrical state of the plasma membrane

(2) metabolism

(3) secretory activity

(4) rate of proliferation and differentiation

(5) contractile or other activities

They are all directly due to alterations of particular cell proteins. Receptor activation by a messenger is only the first step leading to the cell's ultimate response

signal transduction pathways

diverse sequences of events that link receptor activation to cellular responses; the cell-specific mechanisms linked with different messengers

Lipid-soluble messengers

hydrophobic substances such as steroid hormones and thyroid hormone that have nuclear receptors

nuclear receptors

a large family of intracellular receptors.

Sometimes, the inactive receptors are located in the cytosol and move into the nucleus after binding their ligand. Most of the inactive receptors already reside in the cell nucleus, where they bind to and are activated by their respective ligands.

In both cases, receptor activation leads to altered rates of transcription of one or more genes in a particular cell.

more than one gene may be subject to control by a single receptor type

ex. the adrenal gland hormone cortisol acts via its intracellular receptor to activate numerous genes involved in the coordinated control of cellular metabolism and energy balance

the transcription of a gene or genes may be decreased rather than increased by the activated receptor

ex. Cortisol inhibits transcription of several genes whose protein products mediate inflammatory responses that occur following injury or infection; for this reason, cortisol has important anti-inflammatory effects

Water-soluble messengers cannot readily enter cells by diffusion through the lipid bilayer of the plasma membrane

they exert their actions on cells by binding to the extracellular portion of receptor proteins embedded in the plasma membrane

Water-soluble messengers

include most polypeptide hormones, neurotransmitters, and paracrine and autocrine compounds

first messengers

the extracellular chemical messengers (hormones or neurotransmitters) that reach the cell and bind to their specific plasma membrane receptors

second messengers

substances that enter or are generated in the cytoplasm as a result of receptor activation by the first messenger. They diffuse throughout the cell to serve as chemical relays from the plasma membrane to the biochemical machinery inside the cell

protein kinase

an enzyme that phosphorylates other proteins by transferring a phosphate group to them from ATP. Phosphorylation of a protein allosterically changes its tertiary structure and, consequently, alters the protein's activity.

Different proteins respond differently to phosphorylation

some are activated and some are inactivated (inhibited)

Activation of the receptor by a first messenger (the ligand)

results in a conformational change of the receptor such that it forms an open channel through the plasma membrane

receptor tyrosine kinases

receptors that possess intrinsic enzyme activity and specifically phosphorylate tyrosine residues

sequence of events for receptors with intrinsic tyrosine kinase

The binding of a specific messenger to the receptor changes the conformation of the receptor so that its enzymatic portion, located on the cytoplasmic side of the plasma membrane, is activated. This results in autophosphorylation of the receptor; that is, the receptor phosphorylates some of its own tyrosine residues. The newly created phosphotyrosines on the cytoplasmic portion of the receptor then serve as docking sites for cytoplasmic proteins. The bound docking proteins then bind and activate other proteins, which in turn activate one or more signaling pathways within the cell

The common denominator of these pathways

they all involve activation of cytoplasmic proteins by phosphorylation.

exception to the generalization that plasma membrane receptors with inherent enzyme activity function as protein kinases

the receptor functions both as a receptor and as a guanylyl cyclase to catalyze the formation, in the cytoplasm, of a molecule known as cyclic GMP (cGMP). cGMP functions as a second messenger to activate cGMP-dependent protein kinase. These are abundantly expressed in the retina of the eye, where they are important for processing visual inputs.

cGMP-dependent protein kinase

phosphorylates specific proteins that then mediate the cell's response to the original messenger

guanylyl cyclase enzymes are present in the cytoplasm

a first messenger—the gas nitric oxide (NO)—diffuses into the cytosol of the cell and combines with the guanylyl cyclase to trigger the formation of cGMP

janus kinases (JAKs)

a family of separate water-soluble messengers cytoplasmic kinases. The receptor and its associated janus kinase function as a unit

The binding of a first messenger to the receptor

causes a conformational change in the receptor that leads to activation of the janus kinase. The result of these pathways is the synthesis of new proteins, which mediate the cell's response to the first messenger. One significant example of signals mediated primarily via receptors linked to janus kinases are those of the cytokines—proteins secreted by cells of the immune system that have a critical function in immune defenses

G proteins

the largest category of signaling pathways for water-soluble messengers. They contain three subunits, called the alpha, beta, and gamma subunits. The alpha subunit can bind GDP and GTP. The beta and gamma subunits help anchor the alpha subunit in the membrane. They serve as a switch to couple a receptor to an ion channel or to an enzyme in the plasma membrane

Signaling by G protein coupled receptors

The binding of a first messenger to the receptor changes the conformation of the receptor. This activated receptor increases the affinity of the alpha subunit of the G protein for GTP. When bound to GTP, the alpha subunit dissociates from the beta and gamma subunits of the trimeric G protein. This dissociation allows the activated alpha subunit to link up with still another plasma membrane protein, either an ion channel or an enzyme. These ion channels and enzymes are effector proteins that mediate the next steps in the sequence of events leading to the cell's response.

G-protein-coupled receptors

A special class of membrane receptors with an associated GTP binding protein; activation of a G protein-coupled receptor involves dissociation and GTP hydrolysis

Gs

stimulatory G protein

adenylyl (adenylate) cyclase

a plasma membrane enzyme that acts as an effector protein for Gs

cyclic AMP (cAMP)

The activated adenylyl cyclase, with its catalytic site located on the cytosolic surface of the plasma membrane, catalyzes the conversion of cytosolic ATP to 3′,5′-cyclic adenosine monophosphate. It acts as a second messenger

cAMP phosphodiesterase

the enzyme that catalyzes the reaction when cAMP is broken down to AMP. This is subject to physiological control, so the cellular concentration of cAMP can be changed either by altering the rate of its messenger-mediated synthesis or the rate of its phosphodiesterase-mediated breakdown

cAMP-dependent protein kinase

Enzyme that is activated by cyclic AMP and then phosphorylates specific proteins, thereby altering their activity

Common Mechanisms by Which Receptor Activation Influences Ion Channels

The ion channel is part of the receptor.

A G protein directly gates the ion channel.

A G protein gates the ion channel indirectly via production of a second messenger such as cAMP.

phospholipase C

a plasma membrane effector enzyme that catalyzes the breakdown of a plasma membrane phospholipid known as phosphatidylinositol bisphosphate, abbreviated PIP2, to diacylglycerol (DAG) and inositol trisphosphate (IP3). Both DAG and IP3 then function as second messengers but in very different ways.

protein kinase C

a family of related protein kinases which phosphorylates a large number of other proteins, leading to the cell's response. It does not exert its second-messenger function by directly activating a protein kinase, instead cytosolic IP3 binds to receptors located on the endoplasmic reticulum

calcium ion

functions as a second messenger in a great variety of cellular responses to stimuli, both chemical and electrical

Stimulation of a Cell Leads to an Increase in Cytosolic Ca2+ Concentration

Receptor activation:

Plasma-membrane Ca2+ channels open in response to a first messenger; the receptor itself may contain the channel, or the receptor may activate a G protein that opens the channel via a second messenger.

Ca2+ is released from the endoplasmic reticulum; this is typically mediated by IP3⋅

Active Ca2+ transport out of the cell is inhibited by a second messenger.

Opening of voltage-gated Ca2+ channels

Increase in Cytosolic Ca2+ Concentration Induces the Cell's Responses

Ca2+ binds to calmodulin. On binding Ca2+, the calmodulin changes shape and becomes activated, which allows it to activate or inhibit a large variety of enzymes and other proteins. Many of these enzymes are protein kinases.

Ca2+ combines with Ca2+-binding proteins other than calmodulin, altering their functions.

calmodulin

intracellular protein influenced by calcium binding

calmodulin-dependent protein kinases

Activation or inhibition of these leads, via phosphorylation, to activation or inhibition of proteins involved in the cell's ultimate responses to the first messenger.

Eicosanoids

a family of molecules produced from the polyunsaturated fatty acid arachidonic acid. These include the cyclic endoperoxides, the prostaglandins, the thromboxanes, and the leukotrienes. They are generated in many kinds of cells in response to different types of extracellular signals; these include a variety of growth factors, immune defense molecules, and even other eicosanoids, and may act as both extracellular and intracellular messengers, depending on the cell type

Phospholipase A2 (PLA2)

enzyme that splits arachidonic acid from plasma membrane phospholipid and can then be metabolized by two pathways

cyclooxygenase (COX)

an enzyme that initiates one pathway of PLA2 and leads ultimately to formation of the cyclic endoperoxides, prostaglandins, and thromboxanes

lipoxygenase

an enzyme that initiates one pathway of PLA2 and leads ultimately to formation of leukotrienes

Each of the major eicosanoid subdivisions contains more than one member

ex. PGA and PGE for prostaglandins of the A and E types, which then may be further subdivided—for example, PGE2

Aspirin

inhibits cyclooxygenase and, therefore, blocks the synthesis of the endoperoxides, prostaglandins, and thromboxanes

nonsteroidal anti-inflammatory drugs (NSAIDs)

drugs that block cyclooxygenase to reduce pain, fever, and inflammation

ex. aspirin

In addition to the removal of a first messenger, the receptors can be inactivated in at least three other ways

the first messenger may be metabolized by enzymes in its vicinity, or be taken up by cells and destroyed, or it may simply diffuse away. When events such as these happen, the rate of second-messenger production decreases

(1) The receptor becomes chemically altered (usually by phosphorylation), which may decrease its affinity for a first messenger, and so the messenger is released from its receptor

(2) phosphorylation of the receptor may prevent further G-protein binding to the receptor

(3) plasma membrane receptors may be removed when the combination of first messenger and receptor is taken into the cell by endocytosis