1.4. Classification, function and main features of ion channels. Voltage-gated Ca2+ channels. Cellular calcium metabolism.

Question 1

I. Classifications of ion channels
1. What are the 3 classifications of ion channels?

Answer 1

1/ Based on ion charge
2/ Based on cellular localization
3/ Based on gating mechanism

Question 2

I. Classifications of ion channels
2. What are the characteristics of “Based on ion charge” ion channels?

Answer 2

Channels lined with (+) charges permit anions, with (-) charges permit cations

Question 3

I. Classifications of ion channels
3. What are the characteristics of “Based on cellular localization” ion channels?

Answer 3

1/ plasma membrane channels: Na+ -, Ca2+ -, K+-channels
2/ intracellular channels that are classified according to the location of the channels (ex: ER channels – RyR, SERCA)

Question 4

I. Classifications of ion channels
4. What are the 5 types of ion channels based on gating mechanism?

Answer 4

1/ Voltage-gated channels
2/ Ligand-gated channels
3/ Mechano-sensitive channels
4/ Second messenger-gated channels
5/ Heat/light-sensitive channels (less important)

Question 5

I. Classifications of ion channels - based on gating mechanism
4A1. Characteristics of voltage-gated channels

Answer 5

1/ Activated by changes in the electrical membrane potential near the channel (usually activated by depolarization, but sometimes by hyperpolarization)
- Membrane potential alters the conformation of the proteins – opening + closing

2/ Important role in excitable (neuronal/muscular) cells for rapid + coordinated depolarization

Question 6

I. Classifications of ion channels - based on gating mechanism
4A2. Examples of voltage-gated channels

Answer 6

1/ Na+ channels for threshold-activated depolarization phase in neuronal APs, have both a fast activation + slow deactivation gate sensitive to depolarization, which accounts for the timing and shape of the AP
2/ K+channels for repolarization phase in AP
3/ Ca2+ channels, e.g., at synaptic terminals to trigger NT release
4/ Inward-rectified K+channel (KIR) – allows for K+- leakage out of the cell only at very negative membrane potential (~-90mV)

Question 7

I. Classifications of ion channels - based on gating mechanism
4B1. Characteristics of Ligand-gated channels

Answer 7

1/ Activated in response to the binding of a chemical messenger (ligand)
2/ Ligands can be lipids (ex: PIP2), cyclic nucleotides (cAMP), NT (ACh)
3/ Sensors on extracellular side of the membrane (often found in in the synaptic membrane and neuromuscular junctions)

Question 8

I. Classifications of ion channels - based on gating mechanism
4B2. Examples of Ligand-gated channels

Answer 8

nAChR on skeletal muscle that opens in response to ACh binding and allows cations (Na+/K+) through

Question 9

I. Classifications of ion channels - based on gating mechanism
4C1. Characteristics of Mechanosensitive channels

Answer 9

Sensitive to the level of tension in membrane and activated by the deformation

Question 10

I. Classifications of ion channels - based on gating mechanism
4C2. Examples of Mechanosensitive channels

Answer 10

Examples: ones that are found in the cochlear hair cells and on certain touch receptor cells in the skin

Question 11

I. Classifications of ion channels - based on gating mechanism
4D1. Characteristics of Second messenger-gated channels

Answer 11

1/ Controlled by changes of intracellular signaling molecules (ex: cAMP, IP3)
2/ Sensors on intracellular side of the membrane

Question 12

I. Classifications of ion channels - based on gating mechanism
4D2. Examples of Second messenger-gated channels

Answer 12

IP3-receptor on the Sarcoplasmic reticulum (SR) that is activated by IP3

Question 13

I. Classifications of ion channels - based on gating mechanism
4E. Examples of Heat/light-sensitive channels

Answer 13

1/ Light: channel ‘’rhodopsins’’ in the eye
2/ Heat: TRPV1 for sensation of heat in skin q

Question 14

II. What are functions of ion channels

Answer 14

1/ Establishing a resting membrane potential
2/ Builds electrical signals (action potential) by gating the flow of ions
3/ Controlling the flow of ions across a membrane
4/ Regulating the volume

Question 15

III. What are features of ion channels

Answer 15

1/ Arrow, highly specific transmembrane protein pores on the membrane
2/ Passive diffusion: permit diffusion of ions down their electrochemical gradient when open
3/ Gated: a conformational change can be induced to open/close the pore
4/ Selective based on ion charge and ion size
5/ Fast transport – about 4 orders of magnitude faster than carriers (106 – 108 ions/sec)
6/ It cannot really be saturated at normal physiological concentrations (unlike carriers who can be saturated)

Question 16

IV. Ion channels - EXTRA
1A. The role of non-specific cation channels

Answer 16

1/ Can transport Na+, K+, (some of them also Ca2+) ions
2/ Depolarizes the cell

Question 17

IV. Ion channels - EXTRA
1B. The mechanism of non-specific cation channels

Answer 17

1/ Opening of non-specific cation channels depolarizes the cell
2/ Under resting conditions, Na+ influx dominates, K+ efflux is much smaller because of the small driving force
3/ Driving force: the membrane potential minus the equilibrium potential of the particular ion
(Em-EK ~ +10mV
Em-ENa ~ -130 mV
Em-ECa ~ -190 mV )

Question 18

IV. Ion channels - EXTRA
2. The role and mechanism of Cl- channels

Answer 18

1/ In the majority of the cells Em ~ ECl, -> accordingly the driving force for Cl-=0 Therefore opening of the channel under resting conditions results in no ionic current.
=> There are exceptions (e.g. epithelial, smooth muscle cells and some neurons) in which chloride equilibrium potential is more negative than the membrane potential (in this case Cl- channel opening hyperpolarizes)

2/ However, during depolarization of the cell (Em changes), removes from the equilibrium, accordingly, high Cl- conductance counteracts depolarization:

3/ Regulation of Cl- channels:
- Ligand-gated (e.g. GABAA- and glicin-receptors)
- Ca2+-activated
- cAMP-activated (e.g. CFTR)
- mechanosensitive

Question 19

V. Voltage-gated Ca2+ channels
1. What are characteristics of voltage-dependent Ca2+ channels?

Answer 19

• Their structure is similar to that of voltage dependent (Na+) channels
• Not only depolarizes the cell but during its activity, cytoplasmic [Ca2+] also increases -> Ca2+ signal generation

Question 20

V. Voltage-gated Ca2+ channels
2. What is the mechanism of voltage-dependent Ca2+ channels?

Answer 20

Their activation augments depolarization -> it is a self reinforcing process, results in action potential generation or contributes to the depolarizing phase of an action potential or can result in prolonged depolarization

Question 21

V. Voltage-gated Ca2+ channels
3. What is the purpose for classification of Voltage-gated Ca2+ channels?

Answer 21

Purpose of this classification: there are various types which differ in their…
1/ Threshold potential
2/ Speed of inactivation
3/ Conductance
4/ Regulation
5/ Pharmacology

Question 22

V. Voltage-gated Ca2+ channels - Classification of voltage-dependent Ca2+ channels
- What are the 5 types of voltage-dependent Ca2+ channels?

Answer 22

L-type
T-type
N-type
P-type
R-type

Question 23

V. Voltage-gated Ca2+ channels
4A. Location, function and activation voltage of L-type VG Ca2+ channels?

Answer 23

1/ Location: Skeletal + SM, ventricular myocytes
2/ Function: Cardiac AP Plateau, skeletal + SM contraction
3/ Activation voltage: High

Question 24

V. Voltage-gated Ca2+ channels - Classification of voltage-dependent Ca2+ channels
4B. Location, function and activation voltage of T-type VG Ca2+ channels?

Answer 24

1/ Location: SA node
2/ Function: Pacemaker activity
3/ Activation voltage: Low

Question 25

V. Voltage-gated Ca2+ channels - Classification of voltage-dependent Ca2+ channels
4C. Location, function and activation voltage of N-type VG Ca2+ channels?

Answer 25

1/ Location: Brain and PNS
2/ Function: Synaptic NT vesicle release
3/ Activation voltage: High

Question 26

V. Voltage-gated Ca2+ channels - Classification of voltage-dependent Ca2+ channels
4D. Location, function and activation voltage of P-type VG Ca2+ channels?

Answer 26

1/ Location: Cerebellar cells
2/ Function: N/A
3/ Activation voltage: High

Question 27

V. Voltage-gated Ca2+ channels - Classification of voltage-dependent Ca2+ channels
4E. Location, function and activation voltage of R-type VG Ca2+ channels?

Answer 27

1/ Location: neurons
2/ Function: N/A
3/ Activation voltage: intermediate

Question 28

VI. Cellular Ca2+ metabolism
1. What are 2 important channels in Cellular Ca2+ metabolism? What is their mechanism?

Answer 28

• ORAI1 is a Ca2+ release-activated Ca2+ channel protein 1
• STIM1 is so called “stromal interaction molecule 1”

Mechanism:
- STIM1 senses a decrease in [Ca2+]ER, and activates ORAI1 in the plasma membrane
- ORAI1 mediates Ca2+ influx following depletion of intracellular Ca2+ storage and channel activation by the Ca2+ sensor STIM1
- Increase in cytoplasmic [Ca2+] with open Ryanodine Receptor => release even more Ca2+ into cytoplasm

Question 29

VI. Cellular Ca2+ metabolism
2. What is the concentration of Ca2+ in ER?

Answer 29

10^-3 M