3 - Neurotransmission Flashcards
Allosteric modulators only modify the effects of __. When given alone they have __ ___.
Agonists | no effect
Allosteric Modulators (3 points)
- Only modify effects of an agonist and have no effect when given alone.
- Often have greater receptor subtype selectivity than agonists or antagonists.
- Modulators of metabotropic receptors may result in better drugs to treat psychiatric and neurological disorders
- Many Ionotropic and Metabotropic Receptors have additional binding sites called __ __
- Molecules, such as drugs, that bind to such sites and alter functioning of the receptor are called __ __ and can have a positive or a negative effect on receptor signaling
Allosteric Sites | Allosteric Modulators
Some proteins involved in exocytosis are targets for drugs or toxins. __ blocks transmitter release at neuromuscular junctions, causing paralysis. Enzymes in the toxin attack proteins involved in exocytosis
Botulism (a bacterial toxin)
Stimulates protein kinase A (PKA).
Cyclic Adenosine Monophosphate (cAMP)
Regulated by the gas NO; stimulates protein kinase G (PKG).
Cyclic Guanosine Monophosphate (cGMP)
__ __ are important locations for synapses to form
Dendritic Spines
Ca2+ binds to receptors and results in fusion of vesicle membranes with the cell membrane, releasing neurotransmitter molecules into the synaptic cleft
Exocytosis
G proteins act in two ways
- Inhibit or Activate ion channels (ex: K+ channels open, K+ moves out of cell and hyperpolarization results).
-
Stimulate or inhibit Effector Enzymes in cell membrane to synthesize or break down 2nd messenger molecules
- The neurotransmitter molecule is the first messenger.
- 2nd messenger is molecule inside cell that carries out biochemical change signaled by first messenger.
- Consist of 4 or 5 subunits with an ion channel in center
- When transmitter binds to the ___ the channel opens and allows ion flow. This is a __-__ __ __
- __ occurs when channel remains closed despite ligands bound to receptor
- Some __ __ are Na+ channels; result is __ and an __ __ (nicotinic receptor for ACh).
- Others allow Na+ and Ca2+ flow. Ca2+ can act as __ __.
- Others allow flow of Cl–, leading to __ (__ __)
- Ionotropic Receptors
- Receptor | Ligand-Gated Channel Receptor’
- Desensitization
- Ionotropic Receptors | Depolarization and an Excitatory Response
- Second Messenger
- Hyperpolarization (inhibitory Response)
There are two major categories of transmitter receptors
Ionotropic and Metabotropic
Enzymes that transfer a phosphoryl group from a nucleoside triphosphate (ex: Adenosine TriPhosphate)
Kinases
These receptors
- act more slowly, but the response lasts longer.
- consist of one subunit, with 7 transmembrane domains (7-TM receptors).
- work by activating G proteins (G protein- coupled receptors).
Metabotropic receptors
__ __ __ must be packaged into large vesicles in the cell body, so recycling of these vesicles cannot occur at the axon terminal
Neuropeptide Precursor Proteins
Neurotransmitter release is regulated by
- rate of neuron firing
- the probability that vesicles will undergo exocytosis;
- autoreceptors
- reduce the amount of transmitter released;
- they are receptors for same transmitter released by neuron. (e.g., thermostat)
- Neurotrasmitter synthesized and stored in vesicles.
- A wave of depolarization reaches the axon terminals
- Depolarization of presynaptic terminal causes
- Voltage-gated Ca2+ channels to open and Ca2+ rushes into the cell
- Ca2+ causes vesicles to fuse (dock) with presynaptic membrane in the active zone and are primed for release. Various proteins involved.
- Neurotransmitter released into synpatic cleft via Exocytosis
- NT binds to receptor molecules in postsynpatic membrance causing…
- opening or closing of postsynaptic channels
- Postsynaptic current causes excitatory or inhibitory postsunaptic potential that changes exitability of postsynaptic cell
- The vesicle membrane is recycled by endocytosis—the cell membrane buds and pinches off a portion, which then fuses with an endosome.
- Many proteins are involved in exocytosis and vesicle recycling.
- Clathrin coats membrane & initiates invagination/vesicle retrieval
- Synaptobrevin helps vesicle fuse with axon terminal membrane - its the most abundant protein found in synpatic vesicles.
Many neurotransmitters have signaling functions outside the CNS, such as __ __ (__), and __ (__)
Nitric Oxide (NO), and Acetylcholine (ACh)
- Breaks down a phospholipid in cell membrane and liberates two 2nd messengers, ___ and ___
- Together they cause increase in Ca2+ ions in postsynaptic cell and ativation of __ __ __
- Ca2+ acts as a 2nd messenger, but activation of protein kinase requires participation of another protein called __
- Phosphoinositide | Diacylglycerol (DAG) | Inositol trisphosphate (IP3)
- protein kinase C (PKC)
- calmodulin — calcium/calmodulin kinase (CaMK).
Area of the dendritic membrane facing the synaptic cleft with many neurotransmitter receptors
Postsynaptic Density
Neurotransmitters bind to more than one type of receptor because there are __
Drugs can be designed to affect specific __ __ which can result in fewer side effects.
Subtypes | Receptor Subtypes
Receptors are not __. Their role is to pass a signal to the __ __
After binding to a receptor and activating it the transmitter disengages and is free to __, __, or __
Transporters | Pass a Signal | Postsynaptic Cell
bind to another receptor | be inactivated | be reabsorbed.
Recycling mechanisms occur only with small vesicles containing __ __
Classical Transmitters
- __ __ are molecules inside the cell that activate protein kinases to cause __ of substrate proteins
- The added __ groups alter the function of the protein
- Phosphorylation of nuclear proteins can __ __/__ __ __
- Second Messengers | Phosphorylation
- Phosphate
- Turn on/off gene expression
To stop signal transmission, the neurotransmitter molecules must be removed from the synaptic cleft (3 ways)
- Transmitter may be broken down by enzymes — common for ACh, lipid and gaseous transmitters, and neuropeptides
-
Reuptake — transmitters are taken up by the cell that released them.
- Transporter proteins in cell membrane take up transmitter molecules (important for amino acid transmitters).
- Transmitters may be taken up by the postsynaptic cell or astrocytes
__ __ form the basis of almost all actions of psychoactive drugs
They work by a variety of mechanisms:
Synaptic Effects
-
Block storage of NT in synaptic vesicles (making less available):
- Reserpine (for hypertension) blocks storage of DA, NE, and 5-HT in vesicles.
- Can stimulate release of NT by reversing action of uptake transporters:
- Amphetamine stimulates release of DA and NE; fenfluramine stimulates release of 5-HT.
- Can stimulate or inhibit autoreceptors:
- Clonidine and 8-OH-DPAT stimulate autoreceptors for NE and 5-HT, reduce NT release
- pindolol inhibits 5-HT autoreceptors, increases NT release
- Can act on postsynaptic receptors
- Agonist: Mimics NT effect on receptor.
- Benzodiazepines, heroin, morphine, nicotine, THC
- Antagonist: Inhibits effect of NT on the receptor.
- Caffeine; antagonists of D2 receptor used to treat schizophrenia
- Agonist: Mimics NT effect on receptor.
Helps the vesicle fuse with the axon terminal membrane. It is the most abundant protein found in synaptic vessicles.
Synaptobrevin
Triptophan crosses the __ __ __ and turns in to __ in the brain, which converts then to __
Blood Brain Barrier | Seratonin | Melatonin
- Drugs can __ or __ autoreceptors
- Drugs can block storage of __ in __ __, making less available
- Reserpine blocks storage of __, __, and __ in vesicles
- Clonidine and 8-OH-DPAT stimulate autoreceptors for __ and __, reducing release of neurotransmitters
- stimulate | inhibit
- Neurotransmitters | Synaptic Vesicles
- DA | NE | 5-HT
- NE | 5-HT
