Lecture 3 - TRP channels & Glucose-sensing and Feeding Flashcards
What is a TRP channel?
Transient Receptor Potential channel
• Non-selective cation channels – conducting Na+ and K+;
- 2 do not conduct Ca2+ (egTRPM4 and TRPM5); some also permeable to Mg2+
• 6 sub-families of 28 proteins; note 27 proteins in human; found from worm to man
• After activation, membrane is depolarized
• Mutations in human TRP channel genes associated with neurodegenerative diseases, skeletal dysplasia, kidney disorder and pain.
• Expressed in almost all cell types; in excitable and non-excitable tissues
• Present in all cellular membranes, mainly plasma membrane; but not in nuclear envelope or mitochondria
How many sub-families of TRP Channels are there?
TRPC: C for canonical
TRPM: M for melastatin
TRPML: ML for mucolipin
TRPV: V for vanilloid
TRPA: A for ankyrin
TRPP: P for polycystin
How does gustatory signalling occur?
Tastant binds to taste receptors on different receptor cells in taste buds
5 basic tastes:
- sweet (cardohydrates)
- umami (proteins and amino acids)
- bitter (warns about harmful or toxic
environmental compounds)
- salty (osmolytes eg NaCl)
- sour (freshness of foods: avoid rotten materials)
- fatty
- metallic
Food taste and texture: healthy or harmful
What is chemesthesis?
Sensations arising when chemical compounds activate receptors associated with burn-like irritation, stinging (pungent or tingling sensations), pain or thermal sensation – other than taste or smell
What is the structure and function of TRP Channels?
Structure and Topology: much like Kv channels
One subunit: 6 transmembrane segments pore-forming re-entrant S5-S6 loop
Functional channel: 4 subunits required
Physiological functions include:
(1) Sensory functions such as pheromone signalling, taste transduction, nociception and temperature sensation
(2) Homeostatic regulation such as osmoregulation & Ca2+
and Mg2+ reabsorption
(3) Motile functions such as muscle contraction and vasomotor control
What stimuli activate TRP channels?
TRPs activated by
Chemical
Physical
Mechanical stimuli
Gq coupled signalling pathways
Influence Ca2+ entry
- directly or indirectly
Depolarize membrane
- influence AP firing
How do TRP channels enable taste?
Type 2 taste cell:
- activated via endocannabinoids to enhance perception of sweetness by activation of receptor CB1;
- binding of the peptide hormone leptin suppresses taste cell type 2 activity and inhibits sweet taste.
TRPV1, TRPA1 and TRPM8 are expressed on probably all sensory nerve fibres of trigeminal nerve to transduce chemesthetic signals
Piperine from pepper and capsaicin from chilli, camphor from cinnamon activate TRPV1
Heat also activates TRPV1
Allylisothiocyanate (AITC) from mustard and allicin from young raw garlic activate TRPA1
Menthol from mint plant, eucalyptol from eucalyptus tree activate TRPM8
Cold also activates TRPM8
What are the properties of the thermo-TRPs?
thermo-TRPs: expressed in primary sensory nerve terminals: sense and inform on changes in environmental temperatures
6 thermo-TRPS:
TRP vanilloid (TRPV) 1 and 2 –activated by heat at painful level
TRPV 3 and 4 – non-painful warmth
TRP melastatin (TRPM) 8 – non-painful cool temperatures
TRP ankyrin (TRPA) 1 – painful cold
What activates TRPV1?
Activated by wide range of agonists such as low pH, ethanol, lipid such as anandamide and membrane depolarization
-lower pH from 7.6 to 6.4 will sensitize TRPV1 to both heat and capsaicin
Threshold for activation is >43°C.
Threshold here defined as temperature high enough to allow large enough inward currents to trigger firing of action potentials (APs)
- note temperature threshold can be lowered by the action of proinflammatory mediators that are released during tissue injury or inflammation.
Integrator for multiple noxious stimuli
Capsaicin (red) interacts with tyrosine, an aromatic residue (Y511) located in the cytosolic loop linking TM2 and TM3
How come birds and chickens can eat chilli hot?
Capsaicin binding region
Transmembrane domains 2 to 4
Critical residues at and flanking TM3 and partially TM4
8 critical amino acids (indicated in red); Y511 interacts with capsaicin
olvanil: synthetic agonist; CSZ or capsazepine-antagonist
Chilli pepper plants: repel mammalian predators; favour birds as vectors for seed dispersal
Slide 6
How does addition of menthol affect TRPM8 channel activation?
It causes a left shift in activation.
Lower membrane potential is needed for the same number of TRPM8 channels to be open.
Addition of menthol increases inward current by ~>5-fold
What pathways does TRPM2 use to act as a heat sensor for fever?
Thermoregulatory pathways
1. Afferent pathways provide temperature feedback information
2. Efferent regulatory pathways send signals to thermal effector organs to establish thermal homeostasis. Examples of thermal organs are brown adipose tissue (BAT) that generates heat, skeletal muscles that mediate thermogenesis by shivering, and cutaneous blood vessels that regulate heat dissipation.
How are vampire bats able to use infrared-sensing?
Infrared sensors found on the trigeminal nerves, which innervate specialised pit organs on the face of bats, detect infrared signals
TRPV1-S is the potential infrared sensor
Snakes use TRPA1
Ciguatoxin sufferers reported that drinking a cool beer is like hot coffee or a swim in refreshing sea cause burning pain. How does this happen?
Cold allodynia: ciguatoxin modifies and cause opening of NaV channels
- membrane potential becomes -55 mV depolarized from -65 mV
- depolarization induced opening of TRPA1 cause responses to innocuous cold
What are the three components of neuronal response?
– Humoral response: Stimulate hormone release
– Visceromotorresponse: Control autonomic N.S
– Somatic motor response: Elicit regulatory behaviors
