Pathophysiology I - Exam 1, Voltage Gated Ion Channels, Synaptic Transmission

Neurons release ___________ in response to action potentials.

Neurotransmitters

________________ are the signals by which the brain and neurons receive and transmit information to one another through pathways.

Action potentials

What are the three major cations in neurotransmission?

Na+, K+, and Ca2+

What is the major anion in neurotransmission?

Cl-

Active transmembrane countertransport ____ and ____ and the intracellular sequestration and mobilization of ____ permit resting cells to maintain a steady-state concentration of ions that enable electrical depolarization.

Na+ and K+

Ca2+

What is the extracellular concentration of Na+?

140 mM

What is the intracellular concentration of Na+?

14 mM

What is the intracellular concentration of K+?

120 mM

What is the extracellular concentration of K+?

4 mM

What is the intracellular concentration of Ca2+?

100 nM

What is the extracellular concentration of Ca2+?

1 uM

Does increase in permeability to Na+ cause cellular depolarization or hyperpolarization?

Depolarization

T/F: Increase in permeability to K+ causes cellular hyperpolarization.

False; depolarization

Changes in the concentration of what ion is critical to neurotransmitter release?

Ca2+

____ channels are a superfamily of ion channels that are important for maintaining resting potential and are responsible for inhibitory postsynaptic potentials.

Cl-

What is the Cl- concentration outside the cell?

116 mM

What is the Cl- concentration inside the cell?

20 mM

Inactivation of _____ channels leads to hyperexcitability.

Cl-

What are three examples of the neurophysiological roles of ion channels?

(1) Regulation of membrane potential

(2) Volume homeostasis

(3) Regulation of pH of extracellular compartments

Since ________ channels are nonselective and allow ion flow, their activity can result in either depolarization or hyperpolarization.

Cyclic nucleotide-gated (CNG)

CNG channels consist of how many subunits?

Four

What is the difference between alpha CNG channels and beta CNG channels?

Alpha CNG channels are coded for by four genes, while beta CNG channels are coded for by two genes.

______ channels are nonselective ligand-gated cation channels that are encoded for by four genes.

Hyperpolarization-activated cyclic nucleotide-gated channels(HCN)

Where are HCN channels expressed?

Heart and brain

What type of channels have been implicated in epilepsy and neuropathic pain?

HCN

HCN channels open with (hyper/de)polarization and close with (hyper/de)polarization.

Hyperpolarization

Depolarization

How are HCN channels activated?

Binding of cAMP or cGMP

HCN channels play essential roles in ___________ cells and __________ and _________ activity.

Cardiac pacemaker

Rhythmic and oscillatory

_________ channels are a large family of ~28 ion channels that are nonselectively permeable to cations.

Transient receptor potential(TRP)

The name _________________ is unfortunate and does not describe the function of these channels, which is to respond to multiple types of stimuli to allow cation entry into the cell.

Transient receptor potential channel

Transient receptor potential channels to multiple stimuli and function in sensory physiology, including what? (3)

(1) Thermosensation

(2) Osmosensation

(3) Taste

Describe the central concept of neuropsychopharmacology.

Drugs that improve the functional status of patients with neurological or psychiatric diseases typically act by enhancing or blunting neurotransmission in the CNS.

Therapeutic targets of TRP channels include _______ channels that mediate changes in excitability induced by neurotransmitters, ________ receptors that physiologically respond to activation of neurotransmitters, and _________ proteins that clear released transmitter from the extracellular space.

Ion

Neurotransmitter

Transport

What are neurotransmitters?

Endogenous chemicals in the brain that act to enable signaling across a chemical synapse

How many neurotransmitters have been identified?

Over 100

How are central neurotransmitters identified?

(1) The transmitter must be present in the presynaptic terminals of the synapse.

(2) The transmitter must be released from the presynaptic nerve at the same time the nerve is stimulated.

(3) It must be able to be recreated by experimentation.

(4) If available, pharmacological agonists and antagonists should stimulate and block them.

(5) There should be a mechanism to stop them.

What are the two types of neurotransmission?

Fast and slow

T/F: The most common postreceptor events are slow transmission.

False; fast

What type of neurotransmission is primarily the role of G protein-coupled receptors>

Slow

G protein-coupled receptors interect with what type of proteins?

Heterotrimeric GTP-binding

Describe the difference between small-molecule neurotransmitter synthesis and peptide neurotransmitter synthesis.

Small molecule neurotransmitters are synthesized in nerve terminals, while peptide neurotransmitters are synthesized in cell bodies and transported to nerve terminals.

What stores neurotransmitters?

Synaptic vesicles

By what process are neurotransmitters released into the synaptic cleft?

Exocytosis

What are the results of depolarization of a presynaptic neuron?

(1) Vesicle docking at the plasma membrane

(2) Formation of membrane fusion/release complexes

(3) Ca2+ dependent release of vesicle contents

Describe the process of neurotransmitter recognition.

Neurotransmitters diffuse from their release sites and bind selectively to receptor proteins to initiate intracellular signaling in the postsynaptic cell.

What are the different ways neurotransmitter action can be terminated?

(1) Diffusion from the synapse

(2) Enzymatic inactivation

(3) Uptake into neuron and/or glial cell using transporters

How long does fast neurotransmitter response to activation take?

Milliseconds

Describe the process of fast neurotransmission.

(1) Neurotransmitter binds to ligand-gated ion channel on postsynaptic membrane.

(2) Channel opens in response to permeability change

(3) Depolarization or hyperpolarization

How long does slow neurotransmitter response to activation take?

Seconds

________ neurotransmission involves second messengers.

Slow

What are metabotropic receptors?

G protein-coupled receptors

What couple of GPCRs contain seven transmembrane domains?

Metabotropic receptors

How many G protein-coupled receptors are there?

More than 800

What are the five classes of G protein-coupled receptors?

(1) Rhodopsin

(2) Secretin

(3) Glutamate

(4) Adhesion

(5) TAS2 - frizzled/taste receptor 2

Drugs targetting _______ comprises over 1/3 of all pharmaceuticals?

GPCRs

What does peptide neurotransmitter synthesis require that's different than monamine and amino acid synthesis?

DNA transcription to mRNA translated to peptide

What type of neurotransmitters can affect gene expression?

Neuropeptides

How is neuropeptide activity terminated?

Enzymatic inactivation

What type of enzymes deactivate neuropeptides?

Extracellular peptidases

Neuropeptides are deactivated in a specific way; what is a result of this method of deactivation?

Their effects on neuronal signalling can be prolonger

T/F: Neuropeptides are effective as drugs when targetting CNS areas beyond the blood-brain barrier.

False; ineffective

Small molecule antagonists, antibodies against GPCRs, and antibodies against GPCR receptors are all effective treatments against what?

Migraines

How is nitric oxide involved in the CNS? (4)

(1) Long-term potentiation

(2) Activation of soluble guanylyl cylase

(3) Neurotransmitter release

(4) Enhancement of glutamate-mediated neurotoxicity

Where is carbon monoxide generated?

Neurons or glia

What are the two mechanisms for terminating the signaling of released neurotransmitters?

(1) Conversion of the transmitter into an inactive compound via enzymatic reaction

(2) Clearance of neurotransmitter by transport proteins present on neuronal or glial membranes

What's an example of a neurotransmitter being cleared so that it can't act on target receptors? Which transporter does it use?

Dopamine

Dopamine transporter

How many gene families of vesicular neurotransmitter transporters, that sequester neurotransmitters from synaptic vesicles and release them, are there?

Three

__________ transporters have been shown to lower vesicular storage and dopamine release, so they're used to treat involuntary movement disorders like Huntington's chorea and tardive dyskinesia.

Vesicular neurotransmitter transporters

What transporters are well-established targets for therapeutic antidepressants and addictive substances, like cocaine and amphetamines?

Dopamine transporters, norepinephrine transporters, and serotonin transporters

Psychostimulants _______________ and ________________ are the major drugs used to treat ADHD in adults and children.

Methyphenidate

Amphetamine

In ADHD patients, methylphenidate and amphetamine (increase/reduce) and (increase/reduce) attention.

Reduce

Increase

ADHD medications inhibit ______ and ______ transporters, while enhancing ________ and ________ neurotransmission.

Dopamine and norepinephrine transporters

Dopamine and norepinephrine neurotransmission

What are the four core approaches used to identify and develop small-molecule compounds for targeting neuronal signaling?

(1) Synthesizing structural analogues of known neurotransmitters of receptors/channels for target specificity

(2) Using natural products that exist in nature for efficacy

(3) Developing a signaling assay to identify promising functional profiles

(4) Using atomic-level structures of targets to design new compounds