Functional roles of TRP, Cl, Connexins & other channels

Question 1

Discuss TRP channels

Answer 1

TRANSIENT R POTENTIAL (TRP)

-mediates light perception in fly eye

• tetrameric
• 6 TM domains per subunit
• Generate signals by DEPOL. & Ca entry
• Diverse structures & functions, but linked via PLC

Question 2

What are some functions of TRP channels (in general)?

Answer 2

SOMATOSENSATION

• mechano-
• proprio-
• thermoception

-Nociception:
TRPV1
TRPM8
TRPA1

Question 3

Discuss the properties of TRPV1

Answer 3

Venom contains toxins that modulate R/channel function to produce:
-shock
-paralysis
-death
(with ACUTE PAIN & NEUROGENIC INFLAM.)

Earth tiger toxin (DkTx) binds to TRPV1, & is an IRREVERSIBLE AGONIST!

Question 4

Discuss the properties of TRPM8

Answer 4

Activated by MENTHOL and thermal COLD STIM. (synergistic)

Question 5

What do TRPM8-deficient animals show?

Answer 5

No preference for warm vs cold

Question 6

What is important in terms of TRP channel ANTAGONISTS?

Answer 6

May emerge as next generation analgesics

Question 7

Discuss the properties of TRPA1

Answer 7

Detector of CHEM. IRRITANTS & inflame. factors

Activated by pungent agents from mustard (wasabi) and allium (garlic)

Question 8

Why may TRP channels be potential therapeutic targets?

Answer 8

i.e. Block actions of inflame. agents without altering basal heat sensitivity

Question 9

What are Cl channels?

Answer 9

“leak” anion (-) channels that accompany cation (+) channels

Question 10

Name some classes of Cl channels

Answer 10

Cystic Fibrosis Transmembrane Regulator (CFTR)

Voltage-g (ClC)

Ca- Activated (CaCC)

Ligand-g (GABA & GLYCINE Rs)

Question 11

What do Cystic Fibrosis and Myotonia have in common?

Answer 11

Inherited Cl- channel mutations

Question 12

What is cystic fibrosis?

Answer 12

Lung pathology from DECREASED Cl- & bicarb. secretion from submucosal glands

THUS, viscous acidic airway surface liquid (that promotes bacteria colonisation)

Question 13

What is myotonia?

Answer 13

ClC-1 provides the Cl-conductance in SKELETAL MUSCLE, assisting repolarisation after the AP

Inherited mutation in ClC-1 channels!
-exaggerated muscle contraction occur in response to normal stim.

Question 14

DIscuss CaCC channels?

Answer 14

Slowly activated by depolarisation (Cav Ca entry)

Diverse functions:

• fertilisation
• olfaction
• smooth m. contraction
• sensory signal transduction

Regulated by Ca directly, or Ca modulated kinases

Question 15

What are connexion channels?

Answer 15

GAP JUNCTIONS!
(Electrical synapses)

• 6 subunits per channel
• Developmental uncoupling overlaps with period of formation of chem. synapses & an increase in synaptic activity (NMDA Rs)

Question 16

What do electrical synapses allow?

Answer 16

Bidirectional communication

Question 17

What effect do gap junctions have in sub-lethal injury?

Answer 17

Gap junction coupling may assist NEURONAL SURIVAL

-by promoting SPREAD OF PRO-SURVIVAL SIGNALS

Question 18

What effect do gap junctions have in severe brain injury?

Answer 18

Enable SPREAD OF PATHOLOGICAL CONDITIONS

- causing neuronal death
e. g. excitotoxic Ca

Question 19

Discuss inward rectifiers

Answer 19

PLC cascade alters activity of Kir channels, creating the electrical response

2 TRANSMEM. DOMAINS (tetrameric channel)
-GPCRs generate EPSPs BY DECREASING ACTIVITY OF Kir CHANNELS, resulting in increase in excitation of the neuron!