The Biochemical Basis for Therapy: Receptors and Signalling

Question 1

What are receptors?

Answer 1

Sensing elements of chemical communication in the body - neurotransmitters, hormones or other mediators (eg chemokines and cytokines)

Question 2

What is the key characteristic of receptors?

Answer 2

Ligand selectivity

Question 3

What are the 3 types of signalling cells?

Answer 3

Autocrine, paracrine and endocrine

Question 4

What is an autocrine cell?

Answer 4

A cell that signals itself

Question 5

What is a paracrine cell?

Answer 5

A cell that signals its close neighbours

Question 6

What is an endocrine cell?

Answer 6

A cell that signals via molecules transported by the blood to target cells (ie signal molecule is in the circulation)

Question 7

What are the 4 major types of receptors?

Answer 7

Ligand gated ion channels (ionotropic), G-protein coupled receptors (metabotropic), kinase-linked receptors (enzyme-linked) and nuclear receptors

Question 8

What is the location and targeting cells of LGICs?

Answer 8

At the plasma membrane and targeted by hydrophilic signalling molecules (eg fast neurotransmitters) - action of a millisecond timescale

Question 9

What is the location and targeting cells of GPCRs?

Answer 9

At the plasma membrane and targeted by hydrophilic signalling molecules (eg slow neurotransmitters) signal on a second timescale

Question 10

What is the location and targeting cells of kinase-linked receptors?

Answer 10

At the plasma membrane and targeted mainly by hydrophilic protein mediators, worked on an hours time scale

Question 11

What is the location and targeting cells of nuclear receptors?

Answer 11

In nucleus (sometimes in cytoplasm) and targeted mainly by hydrophobic signalling molecules - very slow (hours/days)

Question 12

What are some common hydrophilic signalling molecules?

Answer 12

Acetylcholine, amino acids, amines, peptides, adrenaline and peptide hormones

Question 13

What are some common hydrophobic signalling molecules?

Answer 13

Steroid and thyroid hormones

Question 14

Where does hydrophilic targeting occur?

Answer 14

Extracellularly, usually at the membrane

Question 15

Where does hydrophobic targeting occur?

Answer 15

Intracellularly

Question 16

What are ion channels?

Answer 16

Transmembrane pores formed by glycoproteins that span the membrane to create an ion conducting pathway for selected ions

Question 17

What usually regulates ion channels?

Answer 17

Signals that cause the channel to cycle reversibly between a closed, non-conducting state and an open, conducting conformation = gating

Question 18

What happens when ion channels are open?

Answer 18

Conduct selected ions (passively) down their electrochemical gradients quickly which often mediates very rapid electrical signals

Question 19

What can gate an ion channel?

Answer 19

Chemical signals (eg LGICs), transmembrane voltage (VGICs) and physical stimuli (thermal and mechanical energy)

Question 20

What are the 2 main examples of LGICs?

Answer 20

Nicotonic-acetylcholine receptor (of skeletal muscle) and neurones

Question 21

What is the structure and function of LGICs?

Answer 21

Consists of separate glycoprotein subunits that form a central, ion conducting channel that allows very rapid changes in the permeability of the membrane to certain ions. Come rapidly after the membrane potential

Question 22

What is the sequence of LGIC activation?

Answer 22

Agonist binds = conformational change. Channel opens = conduction pathway for certain ions. Ion flow down the electrochemical gradient

Question 23

What are second messenger systems?

Answer 23

Where receptor activation modulates the activity of an effector, usually an enzyme (or ion channel). The receptors are GPCRs and are linked to effectors by G proteins. Enzyme effectors can increase or decrease the rate of synthesis of second messenger molecules = change in activity of their targets

Question 24

What do ion channel effectors cause?

Answer 24

Changes in membrane electrical properties

Question 25

What is the basic structure of a GPCR?

Answer 25

Integral membrane protein, single polypeptide with extracellular NH2 and intracellular COOH termini, 7 transmembrane alpha-helical spans joined by 3 intra and 3 extracellular loops. Sometimes function as dimers (2 receptors together)

Question 26

What type of proteins are G proteins?

Answer 26

Peripheral membrane protein

Question 27

How many polypeptide subunits do G proteins have?

Answer 27

3 polypeptide subunits (alpha, beta and gamma)

Question 28

What is a special characteristic about the a subunit in G proteins?

Answer 28

in the a subunit there is a guanine nucleotide binding site for GTP or GDP

Question 29

Is there one or multiple type(s) of G proteins?

Answer 29

They exist as multiple types (named in accordance with their a subunit type)

Question 30

How are G proteins activated?

Answer 30

By agonist binding to GPCRs

Question 31

What occupies the guanine binding site in the inactive protein?

Answer 31

GDP

Question 32

What occupies the guanine binding site in the active protein?

Answer 32

GTP

Question 33

What happens when G proteins are activated?

Answer 33

The binding to GPCRs causes a conformational change that is transmitted to the a-subunit which causes guanine nucleotide exchange, subunit dissociation and generates a free GTP-bound a-subunit and By-dimer (both are signalling units)

Question 34

What is guanine nucleotide exchange?

Answer 34

The binding to GPCRs causes a conformational change that is transmitted to the a-subunit which releases GDP and allows GTP to bind in its place

Question 35

What is subunit dissociation?

Answer 35

The binding to GPCRs causes a conformational change that is transmitted to the a-subunit which separates from the receptor and beta-gamma dimer

Question 36

What happens when there is no signalling in GPCRs?

Answer 36

The receptor is unoccupied, the G protein a-subunit binds GDP and the effector isn’t modulated

Question 37

What happens when you turn on the signal in GPCRs?

Answer 37

Agonist activates the receptor which couples with a G protein. Guanine nucleotide exchange, subunit dissociation, G protein a subunit combines with and modifies activity of, effector. Agonist may dissociate by signalling can continue

Question 38

What happens when you turn off the signal in GPCRs?

Answer 38

The a-subunit acts as an enzyme (GTPase) to hydrolyse GTP to GDP and Pi. The signal is turned off. The G protein a-subunit recombines with the By subunit = G protein cycle complete