α4β2α5 nAChR

2023-04-02:

α4β2α5 nAChR #

• The α4β2α5 nicotinic cholinergic receptor in rat brain is resistant to up‐regulation by nicotine in vivo #Read
  • Suggests a regulatory role for α5 nAChR?
  • Subunit Composition and Pharmacology of Two Classes of Striatal Presynaptic Nicotinic Acetylcholine Receptors Mediating Dopamine Release in Mice
    • α5 nAChR knockout: diminished nicotine-sitmulated dopamine release #Ankified
    • The β2 subunit is an absolute requirement for both classes. In contrast, deletion of β4 or α7 subunits had no effect
  • Virtually all of the α5-containing nAChRs in the rat hippocampus, striatum, cerebral cortex, and thalamus are α4β2α5 nAChRs.
  • The α5 subunit is associated in ~37% of the nAChRs in the hippocampus, ~24% of the nAChRs in striatum, and 11–16% of the receptors in the cerebral cortex, thalamus, and superior colliculus.
    • The fact that this resistance to up-regulation was seen in four different brain regions, suggests that it is the presence of the a5 subunit, rather than factors such as specific brain region or cell type that confers this property on a4b2a5 receptors in vivo.
    • Density is not even increased by chronic administration of nicotine.
  • Nicotine-induced increases in nAChRs in brain or neuronal cell lines are not accompanied by changes in subunit mRNAs, nor is de-novo protein synthesis of nAChR subunits required (Penget al.1994; Wanget al.1998).
    • Therefore, studies of the mechanisms underlying nicotine-induced up-regulation of nAChRs have focused on post-translational changes, including:
      • Increased assembly of the subunits intoreceptors (Wanget al.1998; Nashmiet al.2003)
        • The much higher level of nicotine-induced up-regulation in most transfected cells may result from the constant driving force of their constitutively active promoter leading to over-expression of nAChR subunits. Thus, the large nicotine-induced increase in nAChRs seen in most transfected celllines may reflect, to a large extent, enhanced assembly and/orincreased maturation of nascent nAChR oligomers formedfrom excess subunits and, to a lesser extent, decreased receptor degradation.
      • Decreased degradation of the receptors (Peng et al.1994;Wang et al.1998)
        • In brain, where a large excess of subunits is less likely to be the norm, this may be a more important mechanism.
          • α4β2 is perhaps rapidly regraded, while nicotine slows this, leading to upregulation (demonstrated in Peng et al.1994; Kuryatov et al.2005), and α5 may slow this down.
      • Increased maturation of nascent receptors (Kuryatovet al.2005;Salletteet al.2005)
      • Conversion of receptors from alow affinity to a high affinity conformation (Buisson andBertrand 2001; Vallejoet al.2005).
• α5 nAChR lacks a Y190 residue found in all other a subunits (Karlin and Akabas 1995), and without this residue it probably cannot contribute to an agonist binding site.
  • In fact, although α5 has the two cysteine residues at approximately positions 192 and 193 that are common to all nAChR α subunits, it has highest sequence homology with the b3 subunit (Boulter et al. 1990). Thus, the a5 and b3 subunits may represent a branch point at which these two classes of subunits diverged.
    • Interestingly, the presence of β3 in α6β2β3 provides resistance to downregulation by nicotine.
• Ca2+ Permeability of the (α4)3(β2)2 Stoichiometry Greatly Exceeds That of (α4)2(β2)3 Human Acetylcholine Receptors
  • Increased Ca2+ conductance several fold vs. regular α4β2.
    • α4, α5, and β3 subunits all have a homologous glutamate in M2 that contributes to high Ca2+ permeability, whereas β2 has a lysine at this position.
  • We show that Ca2+ permeability is determined by charged amino acids at the extracellular end of the M2 transmembrane domain