Synaptic transmission begins when one brain cell releases a neurochemical into the synapse. The transmission, however, is not complete until that neurochemical binds with a receptor on the postsynaptic, or receiving, neuron. Researchers have learned that receptors are equally as important as the neurochemicals they receive in maintaining healthy neurobiology. In fact, studies have demonstrated that receptors play a critical role in mood, learning, and the formation of social bonds. Many receptors are current targets for drug development for treatment of psychiatric disorders.
What is a receptor?
A receptor is a protein that resides on the membrane of the postsynaptic neuron. The binding of neurotransmitters to receptors is often described using a lock and key metaphor. A “key,” or neurotransmitter, neatly binds with a receptor “lock” resulting in the propagation or dampening of the neural signal (also referred to as the action potential). Receptors, however, are not quite as specific as a single matching lock and key. While scientists had initially hypothesized that a single neuron would only contain one type of neurotransmitter, advances in molecular neurobiology have demonstrated this is not the case. A single neurotransmitter may bind with several types of receptors, even those more commonly associated with a different neurotransmitter, and result in varied reactions depending on their location. So while areas like the basal ganglia, an area linked to risk and reward processing, show a high density of dopamine receptors and the neocortex, the brain region responsible for sensory processing and executive fuction, has a wealth of glutamate receptors, you can find various receptor types spread across the brain. [i]
In addition, other neurochemicals, including hormones, proteins, and peptides, can also bind with receptor proteins.[ii] In any one synapse, there may be hundreds of molecules moving between cells and making alterations to the action potential by interacting with different receptor types.
How do receptors work?
Receptors can result in both direct and indirect effects on synaptic transmission, depending on the receptor type. Ionotropic receptors result in quick, direct effects to signal propagation through ligand-gated ion channels. When a neurotransmitter binds to an ionotropic receptor, it directly opens or closes ion channels at the site of the receptor. Open channels depolarize the cell, propagating the action potential and a release of neurotransmitters to adjacent neurons. Closed channels, on the other hand, hyperpolarize the cell, dampening or even stopping the signal altogether.
[Click here for a visual representation published by the National Center for Biotechnology Information.]
In contrast, metabotropic receptors do not have channels and work in a more indirect fashion through G-protein coupled receptors. When the neurotransmitter connects with the metabotropic receptor, the binding action sets off a chain reaction of protein activity within the cell, altering the cell’s metabolic activity or opening nearby ion channels to either enhance or diminish the cell’s action potential.[iii]
After binding with a specific receptor type, neurotransmitters may also activate so-called second messengers, or other proteins or enzymes within the cell that changes its internal chemistry. Second messengers can moderate action potentials by blocking or opening ion channels, creating new ion channels, or communicating directly with the cell DNA with instructions to produce a new protein.[iv]
How are receptors related to neuropathology and behavior?
Receptors play an important role in both neuropathology and behavior in animals and humans. Neuropsychiatric disease can result from too few or too many receptors in different parts of the brain, leading to too little or too much of a neurotransmitter binding to the postsynaptic cell. Due to the sheer number of possible combinations of neurochemicals within a single synapse, it is difficult to make cause-and-effect statements regarding a single neurotransmitter and a behavior. However, by focusing on the dominant neurotransmitter at any one synapse, researchers have been able to link receptors to behaviors and disease states.
For example, studies have shown that certain types of serotonin receptors are linked to neuropsychiatric disorders, including depression and bipolar disorder. Gene variants of these receptor proteins result in too much neurotransmitter being taking up by both the pre- and postsynaptic cells so not enough transmitter is available at receptors, resulting in the associated neuropathologies. Consequently, researchers have targeted these receptors and others as a potential avenue for drug treatment.[v]
Glutamate, a neurotransmitter known for exciting neurons, is very important in helping to propagate neural signals in the brain. But research has linked its receptors to a variety of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases. When specific receptor types take up too much of this neurotransmitter, it can result in mass cell death and, over time, neurodegeneration results.[vi]
Receptors also affect long-term potentiation, the molecular process that results in learning. The neurotransmitter GABA is a critical inhibitory neurotransmitter in the central nervous system. Recent studies have demonstrated it works in a synapse-specific manner in the hippocampus and plays a critical role in learning and memory. [vii]
Finally, different types of dopamine receptor subtypes, D1 and D2, have been linked to drug addiction, schizophrenia and social relationships. Too many or too few of the different subtypes can result in imbalance in the basal ganglia, an area of the brain responsible for risk and reward processing, leading to problems with addiction. [viii] Certain genetic polymorphisms in the D1 receptor gene, DRD1, confer a higher risk of developing schizophrenia.[ix] D1 and D2 receptors have also been implicated, along with oxytocin receptors, in both the maintenance and formation of social pair bonds, respectively. The density of these receptors in an area of the brain called the nucleus accumbens plays an important role in both mating and social bonds. The D2 type receptor is necessary to initially form the pair bond between two monogamous animals. But for the bond to be maintained over time, there needs to be an adequate density of the D1 variety as well.[x]
[i]Del Arco A and Mora F. Neurotransmitters and prefrontal cortex-limbic system interactions: implications for plasticity and psychiatric disorders. Journal of Neural Transmission. 2009, 116(8): 941-952.
[ii] Kolb B & Whishaw IQ. Fundamentals of Human Neuropsychology. 2009. Worth Publishers, New York.
[iv] Snyder SH. Neurotransmitters, receptors, and second messengers galore in 40 years. The Journal of Neuroscience. 14 October 2009, 29(41): 12717-12721.
[v] Fountoulakis KN, Kelson JR, and Akiskal H. Receptor targets for antidepressant therapy in bipolar disorder. Journal of Affective Disorders. 19 May 2011.
[vi] Raymond LA, Andre VM, Cepeda C, Gladding CM, Milnerwood AJ, and Levine MS. Pathophysiology of Huntington’s disease: time-dependent alterations in synaptic and receptor function. Neuroscience. 27 August 2011.
[vii] Ormond J and Woodin MA. Disinhibition-mediated LTP in the hippocampus is synapse specific. Frontiers in Cellular Neuroscience. 2011, 5:17.
[viii] Eagle DM, Wong JC, Allan ME, Mar AC, Theobald DE and Robbins TW. Contrasting roles for dopamine D1 and D2 receptor subtypes in the dorsomedial striatum but not the nucleus accumbens core during behavioral inhibition in the stop-signal task in rats. Journal of Neuroscience. May 18, 2011, 31(20): 7349-56.
[ix] Zhu F, Yan CX, Wang Q, Zhu YS, Zhao Y, Huang J, Zhang HB, Gao CG and Li SB. An association study between dopamine D1 receptor gene polymorphisms and the risk of schizophrenia. Brain Research. E-publication September 2011.
[x]Aragona BJ, Liu Y, Yu YJ, Curtis JT, Detwiler JM, Insel TR and Wang Z. Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds. Nature Neuroscience. January 2006, 9(1): 133-139.