NAChR subtypes

Historically ganglionic nAChR have been targets for treating hypertension. The discovery of a large family of nAChR subtypes in the CNS, coupled with observations that nicotine has anti-nociceptive, neuro-protective and cognitive effects, has led to the recognition that neuronal nAChR are potential targets... 

The nAChR subtypes vary in response to pharmacological manipulation. The a7 receptors have a low affinity for nicotine and are sensitive to a-bungarotoxin (a-BTX) antagonism, whereas the heteromeric nAChRs are not.14 The p2 containing (p2 asterisk denotes the presence of additional subunits) nAChRs have the highest affinity for nicotine binding and some selectivity for antagonism... 

The earliest studies that attempted to determine whether ct4 subunits formed functional receptors in Xenopus oocytes established that function was obtained only if the oocytes were also injected with either P2 or P4 cDNA, thereby establishing the concept of heteromeric neuronal nAChRs (Deneris et al. 1988, Connolly et al. 1992). The oc4p2 nAChR has been studied extensively because (i) it seems to be the most widely expressed nAChR subtype (ii) it was considered, until recently, to be the highest affinity nAChR and (iii) the number and function of these receptors are altered by chronic nicotine treaUnent. 

Techniques that measure mRNA expression and ligand binding assays that measure receptor expression have been used extensively to identify those nAChR subtypes that are expressed in dopamine neurons. In situ hybridization studies using mouse (Marks et al. 1992 Grady et al. 1997) and rat (Le Novere et al. 1996) brain have detected the mRNAs for all of the known nAChR subunits, except a2 and p4, in... 

Fig. 3 Potential subunit compositions of nAChRs expressed in dopaminergic nerve terminals. A combination of ligand binding ([ H]-epibatidine and [ I]-a-conotoxin Mil), immunoprecipita-tion, and dopamine release data have led to the conclusion that rodent brain expresses a minimum of five different nAChR subtypes. Three of these (the two forms of a4p2 and a4aSP2) do not bind a-conotoxin Mil with high affinity (a-conotoxin Mll-resistant). The three a6-containing subtypes bind a-conotoxin Mil with high affinity (conotoxin Mil-sensitive). In general, the conotoxin-sensitive nAChR subtypes are activated by lower concentrations of agonist than are required to activate the a-conotoxin Mll-resistant subtypes (Salminen et al. 2007)...

The extent of upregulation varies with nAChR subtype and is typically much greater in cell lines than in native tissues after in vivo exposure to nicotine. The P2-containing nAChRs display the highest level of upregulation (Xiao and Kellar 2004), reflecting differences in the interface between adjacent a and p subunits, with respect to p2 versus p4 subunits (Sallette et al. 2004). Interestingly, inclusion of the... 

Epibatidine s antinociceptive effect can be antagonized by pretreatment with the centrally active nAChR antagonist mecamylamine, but not with the peripheral antagonist hexamethonium, so the activation of central nAChRs is presumed to be essential for nicotinic analgesics (Sullivan et al., 1994). The high toxicity of epibatidine has been attributed to its lack of selectivity for specific neuronal nAChR subtypes and has precluded its development as a therapeutic agent. 

Table 2 Selectivity for a7 nAChR subtypes for selected 2-(3-pyridinyl)methyl derivatives...

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