Neurotransmission Proteins

 Neurotransmission Proteins Background

Neurons communicate with each other primarily through unidirectional chemical synapses, where vesicles in the presynaptic nerve terminal fuse with the membrane to release neurotransmitter, which then binds to and activates receptors on the postsynaptic neuron. Understanding the mechanisms of synaptic neurotransmission is the essential to understanding how synapses can be modified, for example in learning and memory or as drug targets. Synaptotagmin plays one of the most important roles in synaptic neurotransmission by serving as the calcium sensor that links calcium entry into the presynaptic terminal to vesicle release.

Neuronal cells are specialized for the propagation of information. These cells are highly compartmentalized and broken into discrete portions that control information flow. Information is encoded electrically, with outgoing signals leaving the cell body, also known as the soma, via a thin insulated process called the axon. Incoming information from other neurons arrives at a complex network of branching processes known as dendrites. At rest the neuronal plasma membrane has an excess of positive charge on the outside of the cell, resulting in a negative membrane potential typically close to -70 mV. The opening and closing of ion-conducting channels allows for transient alterations in membrane potential, which are the basis of electrical signaling. When a neuron is excited the balance of ions that give rise to the resting membrane potential is disrupted. This disruption, while initially confined to soma, spreads to the axon and triggers an all-or-nothing propagation event known as an action potential. The action potential then travels the length of the axon and arrives at synapses.

Synapses are specialized contact points that are typically formed between two neurons (cells can also synapse on themselves). When an action potential arrives at a synapse the action potential can be communicated to the postsynaptic cell either electrically through specialized gap junctions or chemically via the regulated secretion of neurotransmitter molecules. The vast majority of the synapses in the brain are chemical synapses. When chemical neurotransmitters are released from the synaptic terminal they diffuse across the synaptic cleft and bind to postsynaptic receptors. These receptors are either ionotropic receptors, which allow ions into the postsynaptic compartment, or metabotropic receptors, which activate G-protein signaling pathways.


Ionotropic Glutamatergic Neurotransmission

The generation of respiratory rhythm in mammalian brainstem and the neurotransmission of inspiratory drive to respiratory motor neurons involves excitatory synaptic neurotransmission, with excitatory amino acids (EAAs) being the primary transmitter. The most prominent EAA transmitter is glutamate, which binds to both metabotropic and ionotropic receptors. Of interest in this investigation are the ionotropic glutamate receptors, which include the N-methyl-D-aspartate (NMDA) and non-NMDA receptors. NMDA receptors are activated in response to glutamate being bound, resulting in the opening of an ion channel which is nonselective to cations. This allows flow of Na+ and small amounts of Ca2+ into the cell and K+ flow out of the cell, ultimately leading to depolarization and neuronal excitation. Non-NMDA receptors are divided into two subtypes: AMPA and kainate receptors. Like NMDA receptors, AMPA receptors are transmembrane bound for glutamate and mediate fast synaptic neurotransmission in the CNS. Kainate receptors are also involved in excitatory neurotransmission by activating postsynaptic receptors, however; they serve an additional role in inhibitory neurotransmission by modulating the release of the inhibitory neurotransmitter GABA through a presynaptic mechanism. Both NMDA and non-NMDA receptor subtypes appear to be involved in the respiratory control system with both influencing synaptic neurotransmission and regulation of neuronal excitability at the spinal and cranial motor neuron pools, where inspiratory drive transmission is mediated primarily by the postsynaptic action of non-NMDA receptors.


Serotonergic Neurotransmission

Serotonergic neurotransmission is an indispensable mechanism during both the maturation and maintenance of the respiratory control system. During maturation, 5-HT has influences as early as embryonic development. Endogenous 5-HT was demonstrated to be a necessary transmitter in embryonic day 18 (E18) rats since blockade of medullary 5-HT1A receptors induced respiratory arrest, whereas, activating them increased the respiratory frequency. At birth, 5-HT exerts complex effects, including facilitatory effects on the respiratory rhythm generator via medullary 5-HT1A receptors, the recruitment of phrenic motor neurons via 5-HT2A receptors, and inhibitory effects on the transmission of the central drive to phrenic motor neurons via presynaptic 5-HT1B receptors.