House of Mind

"Biology gives you a brain. Life turns it into a mind" - Jeffrey Eugenides

  • 31st July
    2011
  • 31
The Neuromuscular Junction (NMJ) is a specialized synapse that serves to transmit electrical impulses (action potentials) from the motor neuron nerve terminal to the skeletal muscle. Basically, the NMJ allows for efficient and reliable communication between the motor neuron nerve and the muscles required for contraction and movement. The primary chemical messenger in this synapse, which consists of the presynaptic region (containing the nerve terminal), the synaptic cleft and the postsynaptic surface, is acetylcholine. These regions are defined by the differential localization of specific proteins, which underlie their distinct anatomical features and their physiological roles.  Now it’s time to briefly sum up what goes on in the NMJ, as shown in the diagram above.  1. The action potential (or electrical impulse signal) reaches the nerve terminal in the presynaptic region. The hallmark feature of the nerve terminal is that it contains the synaptic vesicles, along with the proteins that help vesicle function. These vesicles are aligned near their release site, called an active zone.  2. When action potentials reach the nerve terminal they activate calcium channels, which open up and facilitate the influx of calcium into the presynaptic terminal, which in turn commences the process of vesicular release into the synaptic cleft.  3. The increase in intracellular calcium concentration triggers the fusion of the synaptic vesicles with the nerve terminal membrane. The mechanism of synaptic vesicle fusion involves conformational changes in multiple docking proteins both on the vesicle and the nerve terminal’s plasma membrane.  4. Once fused with the nerve terminal membrane, the vesicle releases its contents into the extracellular space, also known as the synaptic cleft. The chemical or neurotransmitters (in this case, acetylcholine) released then bind to their corresponding receptors on the postsynaptic surface (also known as the motor end plate in the NMJ).  5 & 6. Acetylcholine binds to its receptors and opens ligand-gated Na+/K+ channels. These structures are designed to optimize cholinergic neurotransmission in order to produce an end plate potential (EPP). The EPP is simply the net synaptic depolarization caused by the release of acetylcholine triggered by the nerve action potential. The EPP is a function of the miniature endplate potential (MEPP) amplitude, which represents the depolarization of the postsynaptic membrane produced by the contents of a single vesicle, and quantal content (number of transmitter vesicles released by a nerve terminal action potential. The EPP serves to open the voltage-gated Na+ channels in the postsynaptic region, which in turn results in an action potential that triggers muscle fiber contraction. These changes in the postsynaptic region potential result in muscle stimulation and contraction. 7. Acetylcholinesterase degrades acetylcholine so that it (choline) can be re-uptaked and recycled to produce new acetylcholine molecules. It’s activity terminates synaptic transmission.  Sources: Hughes, Benjamin W., et. al. 2006. Molecular architecture of the neuromuscular junction. Muscle & Nerve. 33(4): 445-461. DOI 10.1002/mus.20440 Motor Systems: Control of Movement and Behavior. 2008. Available at: http://www.colorado.edu/intphys/Class/IPHY3730/09motorsystems.html

The Neuromuscular Junction (NMJ) is a specialized synapse that serves to transmit electrical impulses (action potentials) from the motor neuron nerve terminal to the skeletal muscle. Basically, the NMJ allows for efficient and reliable communication between the motor neuron nerve and the muscles required for contraction and movement. The primary chemical messenger in this synapse, which consists of the presynaptic region (containing the nerve terminal), the synaptic cleft and the postsynaptic surface, is acetylcholine. These regions are defined by the differential localization of specific proteins, which underlie their distinct anatomical features and their physiological roles. 

Now it’s time to briefly sum up what goes on in the NMJ, as shown in the diagram above. 

1. The action potential (or electrical impulse signal) reaches the nerve terminal in the presynaptic region. The hallmark feature of the nerve terminal is that it contains the synaptic vesicles, along with the proteins that help vesicle function. These vesicles are aligned near their release site, called an active zone. 

2. When action potentials reach the nerve terminal they activate calcium channels, which open up and facilitate the influx of calcium into the presynaptic terminal, which in turn commences the process of vesicular release into the synaptic cleft. 

3. The increase in intracellular calcium concentration triggers the fusion of the synaptic vesicles with the nerve terminal membrane. The mechanism of synaptic vesicle fusion involves conformational changes in multiple docking proteins both on the vesicle and the nerve terminal’s plasma membrane. 

4. Once fused with the nerve terminal membrane, the vesicle releases its contents into the extracellular space, also known as the synaptic cleft. The chemical or neurotransmitters (in this case, acetylcholine) released then bind to their corresponding receptors on the postsynaptic surface (also known as the motor end plate in the NMJ). 

5 & 6. Acetylcholine binds to its receptors and opens ligand-gated Na+/K+ channels. These structures are designed to optimize cholinergic neurotransmission in order to produce an end plate potential (EPP). The EPP is simply the net synaptic depolarization caused by the release of acetylcholine triggered by the nerve action potential. The EPP is a function of the miniature endplate potential (MEPP) amplitude, which represents the depolarization of the postsynaptic membrane produced by the contents of a single vesicle, and quantal content (number of transmitter vesicles released by a nerve terminal action potential. The EPP serves to open the voltage-gated Na+ channels in the postsynaptic region, which in turn results in an action potential that triggers muscle fiber contraction. These changes in the postsynaptic region potential result in muscle stimulation and contraction.

7. Acetylcholinesterase degrades acetylcholine so that it (choline) can be re-uptaked and recycled to produce new acetylcholine molecules. It’s activity terminates synaptic transmission. 

Sources:

Hughes, Benjamin W., et. al. 2006. Molecular architecture of the neuromuscular junction. Muscle & Nerve. 33(4): 445-461. DOI 10.1002/mus.20440

Motor Systems: Control of Movement and Behavior. 2008. Available at: http://www.colorado.edu/intphys/Class/IPHY3730/09motorsystems.html

  • 28th June
    2011
  • 28
GABA: The main inhibitory neurotransmitter in the central nervous system.  GABA is considered part of the small neurotransmitter molecules (like acetylcholine and glutamate) and is synthesized directly in the axon terminal, near the release site. GABA, along with its signaling components, receptors, enzymes, transporters, and such are present early in development.  GABA is a multifunctional molecules with different situational roles throughout development. Functions include: influencing neural migration, acting as a neurotrophic factor and facilitating neurite extension/maturation.  Glutamate is the precursor of GABA. Glutamate is converted into GABA by a decarboxylation reaction catalyzed by glutamic acid decarboxylase (GAD), a rate limiting enzyme in GABA synthesis that requires the cofactor pyridoxal phosphate (PLP). Like glutamate, GABAergic neurotransmission relies on different kinds of receptors (i.e. ionotropic vs. metabotropic) that are characterized by pharmacological differences. There are 3 GABA receptors: GABA-A, GABA-B, GABA-C. GABA-A and GABA-C receptors are ionotropic and mediate fast (inhibitory) GABA responses by triggering calcium channel openings. In other words, they are ligand-gated calcium channels. Bicuculline is a GABA-A receptor antagonist.  GABA-A receptors are classified according to their corresponding amino acid sequence. Additionally, many receptor subunits have been found and each has a unique distribution in the brain. The diversity of GABA-A receptor subtypes are thought to highlight their great importance in the regulation of brain excitability. GABA-A receptors also include binding sites for other clinically relevant drugs (i.e. benzodiazepines). GABA-B receptors are metabotropic receptors that are a part of the g-protein coupled receptor (GPCRs) family and mediate slower GABA responses by activating G-proteins to influence second messenger systems. These mostly regulate calcium and potassium channel openings to mediate the long-term inhibitory actions of GABA. Moreover, GABA-B receptors are present pre and post-synaptically. Baclofen is a GABA-B receptor antagonist.  GABA-B receptors play an important role in long term inhibition of synaptic transmission. GABA-B autoreceptors control the release of GABA while GABA-B heteroreceptors control the release of glutamate, noradrenaline, dopamine, substance P and others. Finally, GABA-B receptor distribution is different than GABA-A receptor distribution in the brain.  GABA-C receptors have a similar structure (pentameric chloride sensitive channels) and composition (different subunits) similar to GABA-A receptors, but vary in their kinetic and pharmacological properties. However, they have greater sensitivity to GABA compared to GABA-A receptors. GABA-C receptors are insensitive to both bicuculline and baclofen (GABA-A and GABA-B antagonists).  Additional roles for GABAergic neurotransmission include: Involvement in mood disorders and psychiatric disorders. For example, GABA agonists are effective antidepressant and antimanic agents, suggesting a GABA deficit. Serving as a developmental signal (see above). Mediating synaptic inhibition. Inhibitory role in motor output structures like the substantia nigra.  Inhibiting DNA synthesis. Sources: Petty, F. 1995. GABA and Mood Disorders: A brief review and hypothesis. Journal of Affective Disorders. 34 (4): 275-281. doi:10.1016/0165-0327(95)00025-I Owens, D.F. & Kriegstein A.R. 2002. Is there more to GABA than synaptic inhibition? Nature Reviews Neuroscience. 3:715-727. doi:10.1038/nrn919 Watanabe, M., et al. 2002. GABA and GABA Receptors in the Central Nervous Systems and Other Organs. International Review of Cytology. 213:1-47. doi:10.1016/S0074-7696(02)13011-7  

GABA: The main inhibitory neurotransmitter in the central nervous system. 

  • GABA is considered part of the small neurotransmitter molecules (like acetylcholine and glutamate) and is synthesized directly in the axon terminal, near the release site.
  • GABA, along with its signaling components, receptors, enzymes, transporters, and such are present early in development. 
  • GABA is a multifunctional molecules with different situational roles throughout development. Functions include: influencing neural migration, acting as a neurotrophic factor and facilitating neurite extension/maturation. 
  • Glutamate is the precursor of GABA. Glutamate is converted into GABA by a decarboxylation reaction catalyzed by glutamic acid decarboxylase (GAD), a rate limiting enzyme in GABA synthesis that requires the cofactor pyridoxal phosphate (PLP).
  • Like glutamate, GABAergic neurotransmission relies on different kinds of receptors (i.e. ionotropic vs. metabotropic) that are characterized by pharmacological differences.
  • There are 3 GABA receptors: GABA-A, GABA-B, GABA-C.
  • GABA-A and GABA-C receptors are ionotropic and mediate fast (inhibitory) GABA responses by triggering calcium channel openings. In other words, they are ligand-gated calcium channels. Bicuculline is a GABA-A receptor antagonist. 
  • GABA-A receptors are classified according to their corresponding amino acid sequence. Additionally, many receptor subunits have been found and each has a unique distribution in the brain. The diversity of GABA-A receptor subtypes are thought to highlight their great importance in the regulation of brain excitability. GABA-A receptors also include binding sites for other clinically relevant drugs (i.e. benzodiazepines).
  • GABA-B receptors are metabotropic receptors that are a part of the g-protein coupled receptor (GPCRs) family and mediate slower GABA responses by activating G-proteins to influence second messenger systems. These mostly regulate calcium and potassium channel openings to mediate the long-term inhibitory actions of GABA. Moreover, GABA-B receptors are present pre and post-synaptically. Baclofen is a GABA-B receptor antagonist. 
  • GABA-B receptors play an important role in long term inhibition of synaptic transmission. GABA-B autoreceptors control the release of GABA while GABA-B heteroreceptors control the release of glutamate, noradrenaline, dopamine, substance P and others. Finally, GABA-B receptor distribution is different than GABA-A receptor distribution in the brain. 
  • GABA-C receptors have a similar structure (pentameric chloride sensitive channels) and composition (different subunits) similar to GABA-A receptors, but vary in their kinetic and pharmacological properties. However, they have greater sensitivity to GABA compared to GABA-A receptors. GABA-C receptors are insensitive to both bicuculline and baclofen (GABA-A and GABA-B antagonists). 

Additional roles for GABAergic neurotransmission include:

  1. Involvement in mood disorders and psychiatric disorders. For example, GABA agonists are effective antidepressant and antimanic agents, suggesting a GABA deficit.
  2. Serving as a developmental signal (see above).
  3. Mediating synaptic inhibition.
  4. Inhibitory role in motor output structures like the substantia nigra. 
  5. Inhibiting DNA synthesis.

Sources:

Petty, F. 1995. GABA and Mood Disorders: A brief review and hypothesis. Journal of Affective Disorders. 34 (4): 275-281. doi:10.1016/0165-0327(95)00025-I

Owens, D.F. & Kriegstein A.R. 2002. Is there more to GABA than synaptic inhibition? Nature Reviews Neuroscience. 3:715-727. doi:10.1038/nrn919

Watanabe, M., et al. 2002. GABA and GABA Receptors in the Central Nervous Systems and Other Organs. International Review of Cytology. 213:1-47.

doi:10.1016/S0074-7696(02)13011-7