An autoreceptor is a receptor located on presynaptic nerve cell membranes and serves as a part of a feedback loop in signal transduction. It is sensitive only to those neurotransmitters or hormones that are released by the neuron in whose membrane the autoreceptor sits.
Canonically, a presynaptic neuron releases the neurotransmitter across a synaptic cleft to be detected by the receptors on a postsynaptic neuron. Autoreceptors on the presynaptic neuron will also detect this neurotransmitter and often function to control internal cell processes, typically inhibiting further release or synthesis of the neurotransmitter. Thus, release of neurotransmitter is regulated by negative feedback. Autoreceptors are usually G protein-coupled receptors (rather than transmitter-gated ion channels) and act via a second messenger.
As an example, norepinephrine released from sympathetic neurons may interact with alpha-2A and alpha-2C receptors to inhibit neurally released norepinephrine. Similarly, acetylcholine released from parasympathetic neurons may interact with muscarinic-2 and muscarinic-4 receptors to inhibit neurally released acetylcholine. An atypical example is given by the β-adrenergic autoreceptor in the sympathetic peripheral nervous system, which acts to increase transmitter release.
Autoreceptors function with TAAR1, a recently discovered GPCR, to regulate monoaminergic systems in the brain. Active TAAR1 opposes the autoreceptor by inactivating the dopamine transporter (DAT). In their review of TAAR1 in monoaminergic systems, Xie and Miller proposed this schematic: synaptic dopamine binds to the dopamine autoreceptor, which activates the DAT. Dopamine enters the presynaptic cells and binds to TAAR1, which increases adenylyl cyclase activity. This eventually allows for the translation of trace amines in the cytoplasm and activation of cyclic nucleotide-gated ion channels, which further activate TAAR1 and dump dopamine into the synapse. Through a series of phosphorylation events related to PKA and PKC, active TAAR1 inactivates DAT, preventing uptake of dopamine from the synapse. The presence of two presynaptic receptors with opposite abilities to regulate monoamine transporter function allows for regulation of the monoaminergic system.
An example of an autoreceptor's functioning occurs in the depression of PPF (post-synaptic potential facilitation). A feedback cell is activated by the (partially) depolarized post-synaptic neuron. The feedback cell releases a neurotransmitter to which the autoreceptor of the presynaptic neuron is receptive. The autoreceptor causes the inhibition of calcium channels (slowing calcium ion influx) and the opening of potassium channels (increasing potassium ion efflux) in the presynaptic membrane. These changes in ion concentration effectively diminish the amount of the original neurotransmitter released by the presynaptic terminal into the synaptic cleft. This causes a final depression on the activity of the postsynaptic neuron. Thus the feedback cycle is complete.
- Bear, Connors, Paradiso (2006). Neuroscience: Exploring the Brain, 3rd edition. p. 119.
- Siegel GJ, Agranoff BW, Albers RW, et al., editors. (1999). "Catecholamine Receptors". Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Lippincott-Raven.
- Xie z, W. S. (2007). "Rhesus Monkey Trace Amine-Associated Receptor 1 Signaling: Enhancement by Monoamine Transporters and Attenuation by the D2 Autoreceptor in Vitro". Journal of Pharmacology and Experimental Therapeutics 321 (1): 116–127. doi:10.1124/jpet.106.116863. PMID 17234900.
- Xie Z, Westmoreland SV, Miller GM (2008). "Modulation of Monoamine Transporters by Common Biogenic Amines via Trace Amine-Associated Receptor 1 and Monoamine Autoreceptors in Human Embryonic Kidney 293 Cells and Brain Synaptosomes". Journal of Pharmacology and Experimental Therapeutics 325 (2): 629–640. doi:10.1124/jpet.107.135079. PMID 18310473.
- Xie Z, Miller GM (2009). "Trace Amine-Associated Receptor 1 as a Monoaminergic Modulator in Brain". Biochemical Pharmacology 78 (9): 1095–1104. doi:10.1016/j.bcp.2009.05.031. PMC 2748138. PMID 19482011.