| A common characteristic of G-protein coupled receptors (GPCRs) is the loss of physiological responsiveness following prolonged agonist exposure or desensitization. In many cases GPCR desensitization is mediated by a well-conserved mechanism involving receptor phosphorylation, internalization, and sorting for degradation or recycling. Clinically, GPCR desensitization is thought to underlie cases of drug-induced tolerance. Although much is known about GPCR desensitization, relatively little is known about GPCR desensitization in polarized cells such as neurons. Due to the specialized nature of neuronal tissue, the location of GPCRs dictates the ultimate effect upon cell signaling. Receptors distributed at axon terminals mediate different processes than the identical receptors located on dendrites, so the preferential regulation of receptors at one site over another can dramatically alter the cellular physiology of a neuron. For example, the selective modification of a presynaptic GPCR would only alter the output through neurotransmitter release; where as manipulation of postsynaptic GPCRs would alter neuronal excitability. Recent studies have shown that desensitization of GPCRs located at synaptic terminals might occur more slowly than GPCRs in non-neuronal systems, which implies that presynaptic and postsynaptic GPCRs may be regulated quite differently at unique subcellular domains. Thus, to understand agonist-induced regulation of GPCRs in vivo, it is important to understand not only the molecular mechanisms involved but also the extent to which these processes contribute to desensitization at distinct locations. Therefore, to test the hypothesis that GPCRs undergo the process of desensitization in CNS neurons occurs differentially at subcellular sites within the same neuron, whole cell electrophysiology recording in cultured neurons measured the physiological activity of receptors located at distinct domains. These studies demonstrated agonist-induced desensitization of endogenous A1 adenosine receptor and GABA-B receptors occurs along a different time course in presynaptic domains than the identical receptor located postsynaptically. Additional experiments demonstrated that A1 adenosine receptors desensitize in a phosphorylation independent manner in neurons. These studies provided the first detailed description of how subcellular localization affects GPCR desensitization in neurons. |
