Receptor desensitisation

A number of other factors activate phospholipase C which causes the hydrolysis of phosphatidyl inositol(4,5)bisphosphate to DAG and IP3. Following release the IP3 is rapidly broken down via IP2 and IP3 to inositol in a Li+ sensitive reaction and this is the reason why lithium can desensitise receptors. The inositol then reacts with activated DAG and is rephosphorylated to regenerate phosphatidyl inositol(4,5)bisphosphate (Berridge and Irvine, 1984 Wakelam, 1989). 

A condition in which a receptor is unresponsive despite the presence of agonist also referred to as a refractory state . Typically this state is the consequence of prolonged exposure to agonist, and occurs after receptor activation it is a built in mechanism to limit a receptor s effects. Mechanistically the desensitised state differs from the resting, closed state of a receptor because in the latter state, a receptor can respond to agonist. This difference predicts that these states are structurally distinct. The desensitised state may also be stabilised by very low concentrations of agonist, such that no measurable activation of the receptor precedes it. Desensitisation is an intrinsic property of many receptors but can also be influenced by other interactions or modifications, such as phosphorylation. 

Figure 3.4 Transmembrane topology of a 7-TM domain G-protein receptor such as the P-adrenoceptor. Agonist binding is predicted to be within the transmembrane domains. The extracellular structure is stabilised by the disulphide bond joining the first and second extracellular loop. The third intracellular loop is the main site of G-protein interaction while the third intracellular loop and carboxy tail are targets for phosphorylation by kinases responsible for initiating receptor desensitisation...

The GABAb receptors were the first G-protein-coupled receptors to be observed to form functional heterodimers (Bowery and Enna 2000) where two G-protein molecules come together to act as a dimer to enhance their combined response. A similar effect has recently also been described for dopamine and somatostatin receptors (Rocheville et al. 2000) and it is likely that this may occur with other G-protein-coupled receptors. The significance of this in terms of the pharmacology of the receptors is unclear, or indeed whether dimerisation affects mechanisms such as desensitisation. 

Heterologous desensitisation refers to the desensitisation of the response to one agonist by the application of a different agonist. For example, desensitisation of a response to adrenaline by application of 5-HT is mediated by protein kinase A or protein kinase C because these kinases can phosphorylate receptors which are not occupied by agonist. Phosphorylation disrupts the receptor-G-protein interaction and induces the binding of specific proteins, arrestins which enhance receptors internalisation via clathrin-coated pits. Thus desensitisation of G-protein-coupled receptors results in a decrease in the number of functional receptors on the cell surface. 

What the overall physiological consequences of either an increase or decrease in 5-HT transmission in any brain region might be is beyond the scope of this chapter. However, it is certain that the diverse cocktail of 5-HT receptors in every brain region gives scope for flexibility and refinement in the 5-HT response that would not be possible if there were only the two receptors identified by Gaddum. This flexibility applies not only to the qualitative features of the response but also its duration. Another dimension of sophistication is added by the different affinities of 5-HT for each of its receptors and differences in their rates of desensitisation. An interesting discussion of how all these variables could affect overall 5-HT transmission in the brain can be found in Uphouse (1997). 

The reason for this disappointing response is uncertain but may be due to desensitisation of the GABAa receptors, or the actual inhibition of GABA inhibitory neurons through somatic autoreceptors which could disrupt the precise timing of physiological inhibition. Activation of the GABAb receptor with baclofen has no... 

Figure 20.6 Schematic representation of the effects of 5-HT reuptake inhibitors on serotonergic neurons, (a) 5-HT is released at the somatodendritic level and by proximal segments of serotonergic axons within the Raphe nuclei and taken up by the 5-HT transporter. In these conditions there is little tonic activation of somatodendritic 5-HTia autoreceptors. At nerve terminals 5-HTib receptors control the 5-HT synthesis and release in a local manner, (b) The blockade of the 5-HT transporter at the level of the Raphe nuclei elevates the concentration of extraneuronal 5-HT to an extent that activates somatodendritic autoreceptors (5-HTia). This leads to neuronal hyperpolarisation, reduction of the discharge rate and reduction of 5-HT release by forebrain terminals, (c) The exposure to an enhanced extracellular 5-HT concentration produced by continuous treatment with SSRIs desensitises Raphe 5-HTia autoreceptors. The reduced 5-HTia function enables serotonergic neurons to recover cell firing and terminal release. Under these conditions, the SSRI-induced blockade of the 5-HT transporter in forebrain nerve terminals results in extracellular 5-HT increases larger than those observed after a single treatment with SSRIs. (Figure and legend taken from Hervas et al. 1999 with permission)...

More importantly for this discussion is the finding that chronic administration of an antidepressant produces a similar increase in the concentration of extracellular 5-HT in the terminal field together with recovery of neuronal firing. Presumably this is because the prolonged elevation of extracellular 5-HT around the neurons in the Raphe causes progressive desensitisation of the somatodendritic 5-HTia receptors. At this point, inhibition of their firing does not occur and so more 5-HT is released in the cortex (see Hervas et al. 1999). 

A related strategy would be to inactivate the 5-HTib/id autoreceptors which are found on serotonergic nerve terminals and so prevent feedback inhibition of 5-HT release in the terminal field. These drugs would not prevent the impact of indirect activation of 5-HTia receptors, and the reduced neuronal firing, by SSRIs (described above), but they would augment 5-HT release in the terminal field once the presynaptic 5-HTia receptors have desensitised. Selective 5-HTib/id antagonists have been developed only recently but will doubtless soon be tested in humans. 

Inhaled nicotine is efficiently delivered to the brain (see chapter by Benowitz, this volume) where it selectively interacts with its central targets, the neuronal nicotinic acetylcholine receptors (nAChRs). The multiple subtypes of uAChR (see chapter by Collins et al, this volume) all bind nicotine but with different affinities, depending on the subunit composition of the uAChR. Binding may result in activation or desensitisation of uAChRs, reflecting the temporal characteristics of nicotine dehvery and local concentration of nicotine. Another level of complexity of the actions of nicotine reflects the widespread and non-uniform distribution of uAChR subtypes within the brain, such that nicotine can influence many centrally regulated functions in addition to the reward systems. In this chapter, we address the consequences of nicotine interactions with nAChRs at the molecular, cellular and anatomical levels. We critically evaluate experimental approaches, with respect to their relevance to human smoking, and contrast the acute and chronic effects of nicotine. 

VR1 is a polytopic protein containing six transmembrane segments with an additional short hydrophobic stretch between transmembrane regions 5 and 6, which is believed to be associated with the channel pore. There are three possible protein kinase A phosphorylation sites on the VR1 that might play a role in receptor desensitisation. 

The Desensitisation as A3 Adenosine Receptor Regulation Physiopathological Implications... 

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