2 - Neuronal Ion Channels and Disease Flashcards
How many neurons are in our nervous system?
85 Billion
How many synapses are in our nervous system
Over 100 Trillion
Model Neuron Components
Input (Dendrites)
Integration (Dendritic Tree & Cell Body)
Action Potential Initiation (Axon Hillock)
Conduction (Myelinated Axon)
Output (Synaptic Bouton)
3 types of electrical signal responses from different neuronal populations
No Adaptation (Fire Continuously)
Adaptation (Fire, then slow their firing rate)
Pacemaker (No excitatory input required)
Ion Channels - 2 Essential Properties
Gating (Open or closed)
Permeation (Selectivity and conductance of ion flow through the channel)
4 types of Ion Channel gating
Voltage Gated
Ligand Gated (Extracellular Ligand)
Ligand Gated (Intracellular Ligand)
Stress Activated
Sodium Potassium Pump - Function
Keep K+ in and Na+ out
Keep inside more (-) than outside
Reversal Potential
The point at which Na+ no longer feels a drive into the cell
Potassium Channel Structure
Tetramer Each subunit has: Intracellular N-Terminus 6 Transmembrane regions Intracellular C-Terminus
On a Potassium Channel subunit, what senses the voltage change?
Transmembrane Regions 1 - 4
On a Potassium Channel subunit, what forms the pore, itself?
Transmembrane Regions 5 & 6
Sodium Channel Structure
Single subunit with long intracellular/extracellular regions dividing the channel into 4 domains that behave like a tetramer, even though they’re technically all connected.
Comes with lots of proteins and junk to regulate the channel’s activity
Calcium Channel Structure
Like a Sodium Channel. Four domains stitched together for the main pore-forming Alpha-1 Subunit, with auxiliary subunits (like Beta-1) crucial for getting the channel to the cell surface.
Why do Calcium Channels need a Beta subunit?
To reach the cell surface
Inward Rectifier Potassium Channels
Open in basal state. Think “leak channels” from Mowsh.
2 types of Voltage Gated Calcium Channels
Low Voltage Activated (T-Type)
High Voltage Activated (L-Type, P/Q-Type, N-Type, R-Type)
Nodes of Ranvier contain high concentration of
Voltage Gated Sodium Channels
Presynaptic Terminus contains high concentration of
Voltage Gated Calcium Channels
Diseases Linked to Calcium Channels
Autism
Epilepsy
Self-Biting Behavior
Neuropathic Pain
Diseases Linked to Potassium Channels
Long QT Syndrome
Paralysis
Diabetes
Diseases Linked to Sodium Channels
Long QT Syndrome
Epilepsy
Cardiac Arrhythmias
Pain
4 main ways Voltage-Gated Ion Channels go bad
Mutations (Ion channelopathies)
Autoimmune Diseases
Defects in expression level
Mislocation within cell
Painful Sodium Channelopathies
Inherited Erythromelagia PEPD Overlap Syndrome Channelopathy associated insensitivity to pain Painful peripheral neuropathies
Inherited Erythromelagia - Channel & Mutation
Nav1.7 - Gain of function, primarily enhanced activation
Inherited Erythromelagia - Pattern
Pain - Distal limbs (intense burning & flushing)
PEPD (Paroxysmal Extreme Pain Disorder) - Channel & Mutation
Nav1.7 - Gain of function, primarily impaired fast-activation
PEPD (Paroxysmal Extreme Pain Disorder) - Pattern
Pain - Perirectal, periorbital, perimandibular
Overlap Syndrome - Channel & Mutation
Nav1.7 - Enhanced activation + impaired fast-inactivation
Overlap Syndrome - Pattern
Mixed
Channelopathy associated insensitivity to pain - Channel & Mutation
Nav1.7 - Loss of Function
Painful Peripheral Neuropathies - Channel & Mutation
Nav1.7 OR Nav1.8 - Gain of function, multiple effects on channel
Painful Peripheral Neuropathies - Pattern
Early pain usually distal
Painful Na Channelopathies - Typical Channel
Nav1.7
Sodium Channel Speeds (In Health)
Fast Activation
Fast Inactivation
Generalized Epilepsy with Febrile Seizures - Mutation
Altered channel inactivation (Alpha and/or Beta-1 subunits) causing persistent inward current
Multiple Sclerosis - Proposed Mechanism
Demyelination disease
Sodium channels more widely distributed
Increased Nav1.6 sodium influx
Na+/Ca++ Exchanger compensates, leaving us with high intracellular calcium
Kv7.1 Channels - Location
Heart & Inner Ear
Leading cause of Long QT Syndrome
Kv7.1 Mutation leading to exertion-triggered cardiac arrhythmias
Retigabine
Makes Potassium Channels unresponsibe, no longer fire action potentials
M Channels
Regulated by Muscarinic Receptor activation
Kv7.2 and Kv7.3
Heterotetramers that cause BFNS
BFNS
Benign Family Neonatal Seizures - A loss of function mutation in potassium channels Kv7.2 and Kv7.3
Queen of Ion Channels
Calcium Channels - Beyond contributing to the electrical properties of the neuron, they serve as the bridge between electrical and chemical signals
Cav2.1 Channelopathies
Familial Hemiplegic Migraine
Episodic Ataxia Type 2
Familial Hemiplegic Migraine
Migraines with weakness on one side of the body, can last up to weeks. From a Cav2.1 Channelopathy (missense mutation). Sometimes acompnaies by coma and ataxia
Episodic Ataxia Type 2
Severe discoordination of motor activities. From a Cav2.1 Channelopathy via truncation or incorrect splicing, leading to a nonfunctional Cav2.1 channel.
Cav1.2 Channelopathy
Timothy Syndrome
Timothy Syndrome
Multisystem - Including Arrhythmias, Autism, Abnormal Facial Features, Webbed Fingers. From a subtle gain-of-function mutation in Cav1.2, allowing slightly more Calcium in after inactivation
Opiate Analgesia Mechanism of Action
Acts on GPCR on presynaptic terminus, which sends 2nd messenger to inhibit Ca2+ channel.
Medical Marijuana Mechanism of Action
Acts on cannabinoid receptors, which inhibit voltage-gated Ca2+ channels, reducing synaptic release.
Target of Gabapentin
Alpha-2-delta subunit of Cav channels
Gabapentin
Treats neuropathic pain and epilepsy
