Quiz 4 Synapses & vesicles, receptors

What are receptors?

Proteins that are capable of sending a signal to change the function or activity of a neuron. They are large transmembrane proteins. Ligands (aka signaling molecule, aka neurotransmitter, or drug) bind to the part of the receptor on the extracellular side. Receptors are specific for their ligand or neurotransmitter

Types of postsynaptic receptors

Ligand-gated ion channel (ionotropic). G-protein coupled receptors (metabotropic)

Ionotropic Receptors

Also known as ligand-gated ion channel receptors (that we have seen before when discussing ion channels). In the diagram the neurotransmitter stays on the extracellular side, ONLY ions pass through. Induce a change in membrane potential (EPSP or IPSP)

Metabotropic Receptors-GPCRs

Also known as GPCRs - G-protein coupled receptors. They act SLOWER than ligand-gated ion channel receptors. They produce a modulatory signal. Instead of allowing ions though they begin a signaling cascade inside the neuron. They are also transmembrane proteins with a very specific structure - they span the membrane 7 times. On the intracellular side, the receptor is linked to a G-protein. There are different types of G-protein alpha subunits

GPCRs

GPCRs need energy to move around the different molecules. Instead of ATP it uses GTP. When the neurotransmitter binds, GDP is exchanged for GTP. Then the alpha subunits will detach with GTP attached and will start a signaling cascade. The beta and gamma subunits usually stick together and either stay attached to the membrane or activate a different signaling cascade.

Metabotropic Receptors - GPCRs - Alpha Subunits

Galphas: s is for stimulatory. These receptors increase activity of an enzyme called adenylyl cyclase, cyclic AMP, and PKA. Galphai: i is for inhibitory. These receptors decrease activity of adenylyl cyclase, cAMP, and PKA. Galphaq: generally excitatory activates different enzymes compared to Galphas

Autoreceptors

On occasion a neurotransmitter may have receptors on the presynaptic side (on the membrane of the axon terminal). These receptors are often inhibitory and serve a self-regulatory function. They can often decrease or increase neurotransmitter release from that axon terminal

Electrical Synapses

Cells share their cytoplasm and there is an exchange of ions and other small molecules (ATP). Related to the reticular theory that was proposed by Golgi. Channel connects the two neurons - made of proteins called connexis.

Electrical Synapses or Gap Junctions

Can pass information bidirectionally. Sometimes referred to as gap junction-mediated connections. The most thoroughly studied electrical synapses occur between excitatory projection neurons of the inferior olivary nucleus and between inhibitory interneurons of the neocortex, hippocampus, and thalamus.

Clinical Application: Charcot- Marie- Tooth (CMT) disease

Rare genetic disorder that damages part of the PNS. Results in muscle weakness, difficulty walking, experience abnormal sensations (tingling and pain in extremities). A connexin protein - Cx32, is heavily expressed in Schwann cells. Mutations in Cx32 are associated with the X-linked form of CMT.

Chemical Synapses

Signaling molecule (neurotransmitter) is released from the presynaptic neuron, diffuses across the synapse, and binds to its corresponding receptors. Chemical synapse about 20-40nm wide. Depending on the neurotransmitter released and the corresponding receptors, a variety of responses can be produced. A specific synapse between neurons and muscles are called the NMJ or neuromuscular junction

Small vesicles (often clear)

About 40nm wide. Although small, 1000-10’s of thousands of molecules of NT stored in each one. Found exclusively in axon terminals. Classical NTs like glutamate, GABA, dopamine, norepinephrine.

Large Dense Core Vesicles

About 100-250nm wide. Store peptide NTs like dynorphin or enkephalin. Packaged near the nucleus so can be found throughout neuron.

How are vesicles packaged with NT?

Transmembrane proteins called vesicular transporters help fill the vesicles with neurotransmitters. Tranporter is specific for the neurotransmitter it lets in. vAChT=vesicular acetylcholine transporter. The transport of NT into the vesicle is aided by vesicular ATPases and antiporters.

Where are vesicles found in the axon terminal?

Readily releasable pool (RRP), Recycling pool, Reserve pool

Readily releasable pool (RRP)

Located close to the membrane, some already docked. Neurotransmitter is released from this pool first.

Recycling Pool

Depleted due to release of NT. In process of being refilled or reloaded with NT.

Reserve pool

Furthest from membrane. Most vesicles found here

Chemical Communication (1)

The pre-synaptic neuron stores transmitter in vesicles, waiting to be released when an action potential (AP) reaches the pre-synaptic terminal

Chemical Communication (2)

The AP causes voltage-gated Ca 2+ channels to open. This initiates the release of neurotransmitter into the synaptic cleft

Chemical Communication (3)

The transmitter binds to post-synaptic receptors, producing an electrical change

Three types of postsynaptic response

EPSP = excitatory post synaptic potential, IPSP= inhibitory post-synaptic potential, Neuromodulation

EPSP = Excitatory post-synaptic potential

Brief electrical change to excite neuron, AP more likely

IPSP = inhibitory post synaptic potential

Brief electrical change to inhibit neuron. AP less likely

Neuromodulation

Change in intracellular signaling that modulates neuronal function more long-term

Chemical Communication (4)

The AP has ended all transmitter has been broken down by degrading enzymes or taken back up into axon terminal through reuptake transporters. If the post-synaptic neuron did not reach threshold it returns to rest.

How are neurotransmitters stored and released? (1)

Proteins on the vesicle and the presynaptic cell membrane bind to each other, docking the vesicle

How are neurotransmitters stored and released? (2)

When Ca2+ enters, it binds to docking proteins and activates vesicle fusion

How are neurotransmitters stored and released? (3)

Neurotransmitters from the vesicle flow into the synaptic cleft

How are neurotransmitters stored and released? (5)

Neurotransmitter bind to postsynaptic receptors, causing EPSPs, IPSPs and/or secondary biochemical processes

Release of Neurotransmitter from Vesicles

There are many proteins, called SNARE proteins, that are found on vesicles and on the plasma membrane of the axon terminal to make this happen. V-Snares, T-Snares. The v- and t- snares from a complex to allow vesicles to release NT.

V-Snares: V for vesicular

Synaptotagmin: detects a rise in calcium (from the v-g Ca2+ channels). Synaptobrevin

T-Snares: T for target (on the plasma membrane of AT)

Syntaxin, SNAP-25