Neurotransmitter Proteins

 Neurotransmitter Proteins Background

Neurotransmitter is the mediator between neutrons communications. These moleculars include catecholamines, excitatory amino acids, GABA, serotonin and so on. Neurotransmitter is also known as chemical messengers which function to enable neurotransmission. These messengers are released from synaptic vesicles in synapses into the synaptic cleft, received by receptors on the target cells.


The mechanism of neurotransmitter release

The fusion of vesicles from presynaptic neurons, or exocytosis, is a tightly regulated, albeit, not fully understood process. The underlying mechanisms of this process are conserved across animal phyla and the molecular machinery has been conserved from yeast to neurons. Release of transmitter follows the action potential invasion of the presynaptic terminal. This depolarization opens various voltage-operated Ca2+ channels. On entry into the presynaptic terminal, Ca2+ then binds to a closely associated low affinity Ca2+-binding protein at concentrations of tens or hundreds of micromolar to trigger transmitter release. A complex, but rapid, orchestration of proteins associated with the transmitter-containing vesicle is then activated to cause fusion of the vesicle with the cell membrane of the terminal and release of transmitter. The membrane fusion event between vesicle and the plasmalemma is governed by a variety of protein families. Although this list is constantly being appended, the foremost among these is the SNARE (soluble NSF (N-ethylmaleimide-sensitive factor) attachment receptor) family of proteins, which assemble into specific complexes and drive lipid bilayer fusion.


Neurotransmitter receptors

Neurotransmitter receptors play a significant role in the controlled movement of specific ions across the cell membrane. Upon binding of neurotransmitter ligands, these receptors form open transmembrane channels that conduct specific ions across the membrane down the electrochemical gradient. Based on the diameter of the channel pore and the nature of the R groups lining the channel pore, specific cations or anions are selectively permeable in specific types of neurotransmitter receptor channels.

The influx of cations, such as Na+ ions across the neurotransmitter receptor channels upon binding of specific ligands causes the postsynaptic cell to be depolarized from the resting membrane potential. Due to the movement of cations into the cell, the net membrane potential rises from its resting membrane potential of -60 mV to a more positive value, hence reaching the threshold value range of -55 mV to -40 mV, which results in the generation of action potential. If the net membrane potential increases as a consequence of cation influx and the action potential is generated resulting in cell communication, this effect is termed excitatory.

The inhibitory effect, on the other hand, occurs when the membrane potential decreases away from the action potential threshold value for neurotransmitter receptors, which are specifically permeable to anions such as Cl- ions. For example, since the Cl- ions concentration is higher in the extracellular side relative to the intracellular side, when the neurotransmitter receptors form transmembrane channels that are specifically permeable to Cl- ions channels, the net result of the influx of Cl- into the cell would be to hyperpolarize the postsynaptic cell away from its resting membrane potential. Hence an action potential is prevented from firing.


Types of Neurotransmitter Receptors

Excitatory Neurotransmitter Receptors: Glutamate receptors constitute the principal excitatory transmitter receptors in the mammalian brain. These receptors can be classified into two categories, namely the ionotropic glutamate receptors (iGluR), which are ligand gated ion channels and the metabotropic glutamate receptors (mGluR), which are G-protein coupled receptors. The iGluRs, which are of significant interest to us, can be broken down into three subgroups based on pharmacological properties, amino acid sequences and functional behavior. These subtypes include a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, composed of different combination of GluRl-4 subunits, kainate (Kai) receptors that are formed by low affinity GluR5-7 and high affinity KA1-2 subunits and N-methyl-D-aspartate (NMDA) receptors that consist of NMDA1, NMDA2a-d subunits.

Inhibitory Neurotransmitter Receptors: The function of an inhibitory receptor is such that it inhibits the perpetuated transmission of excitatory signals. Since an action potential is generated when the membrane potential exceeds the threshold value of - 55 mV to - 40 mV and produces a net potential that is more positive, the inhibitory receptors which selectively control the movement of anions, mediates inhibitory currents that cause the potential to move away from the threshold value to a net potential that is more negative (~ -75 mV). Hence the neuron is prevented from firing an action potential. The principle inhibitory neurotransmitter in the central nervous system is yaminobutyric acid (GABA). γ-Aminobutyric acid (GABA), which can be found in abundance throughout the mammalian brain, is known to act on two specific types of receptors. The first type is the GABAA receptors that are widely distributed throughout the mammalian brain. The second type is the GABAB receptors, which are members of the G-protein linked family of receptors. These receptors are activated by at least two molecules of GABA and by naturally occurring and synthetic structural analogs, such as muscimol and isoguvacine respectively, to regulate the gating of the chloride ion channel.