misc

Question 1

Effect of the beta subunit on the alpha in VGICs

Answer 1

Alpha subunits can function on their own; the accessory or beta subunits are more diverse and modulate the function of the alpha.

• can regulate expression levels, location and trafficking
• can alter voltage dependence of activation or inactivation
• can bind drugs that modulate function
• phosphorylation of beta su can regulate VGIC functions

Question 2

Molecular Properties of VGICs

Answer 2

• Aqueous pore that controls selectivity for Na+/K+/Ca2+ ions
• All VGICs have similar pore structure
• K+ channels are 100-1000 fold selective over K+
• Na+ channels are 10fold selective for Na+ over K+
• Ca2+ channels are 1000 fold selective for Ca2+ over other cations

Question 3

Opening and closing of VGICs

Answer 3

• VGIC open in response to changes in membrane potential
• VGICs contain a voltage sensor, which moves in response to changes in membrane potential
• Regulatory domains in some related channels can regulate opening of channels - e.g. Ca2+ activated K+ channels, cAMP regulated K+ channels
• Deactivation: when the membrane potential reverses back to its resting state the channel may close (opposite of activation)
• Inactivation: voltage dependent Na+ channels will close immediately after being activated (even when there is still depolarisation). Ball and chain model for inactivation - influx of +ve charge will cause an intracellular domain to swing into the open pore of the channel to prevent ion flow.

Question 4

Regulation of VGICs

Answer 4

• Phosphorylation of VGICs can alter the channel properties such that it responds in a different manner to allow the cell to respond to different physiological stimuli - allows for rapid changes in channel function (seconds or less)
• e.g. PKC causes phosphorylation of a single residue in the alpha su of a Na_v, to slow the rate of channel inactivation
• e.g. PKA phosphorylation slows the rate of Ca_v channel activation and shifts the voltage dependence so that it is activated at more negative potentials

Question 5

Drug Modulation of Na_v activity

Answer 5

• Blocking all Nav channels would have major unwanted side effects - complete loss of sensory system, sedations, coma
• Therapeutic effects can be achieved through selective modulation of Nav channel subtypes
• Many Nav blocking drugs gain access to the channel by binding to the open state of the pore - ie only active neurones
• Rates of activation and inactivation are key to determining selectivity