Functional Changes to the Modulation of α4β2* Nicotinic Acetylcholine Receptors during Postnatal Maturation

Abstract

The neurotransmitter acetylcholine (ACh) acting at its α4β2* subtype of nicotinic acetylcholine receptor (nAChR) within the cerebral cortex plays an important role to support cognitive functions. ACh normally initiates a robust excitatory response at α4β2* nAChRs, although this activity may be modulated by a number of mechanisms that alter receptor function. Negative receptor modulation may occur via desensitization by the competitive agonist nicotine or via presumed negative allosteric modulation by the endogenous progesterone‐derived neurosteroid 3α‐hydroxy‐5α‐prenan‐20‐one (allopregnanolone; ALLO). Conversely, positive modulation may occur via positive allosteric modulation by the alkaloid galantamine. Although each form of modulation has been demonstrated to occur in α4β2* nAChRs located on pyramidal neurons within layer VI of the medial prefrontal cortex (mPFC) in young postnatal male mice, the presence and relative strength of modulation in young postnatal female mice, and at maturity for both sexes, is unclear. Using whole‐cell electrophysiology in mFPC layer VI neurons, we measured the ability of nicotine (300 nM), ALLO (10 μM), and galantamine (0.1 μM) to modulate ACh activation of α4β2* nAChRs in male and female mice at postnatal day (P)15‐20 (young postnatal age) and P80‐120 (adulthood). For nicotine, nAChR desensitization at P15‐20 was greater than at P80‐120 and this result was driven by an effect of postnatal age in male mice only. In contrast, ALLO inhibited nAChR function to a similar degree at both P15‐20 and P80‐120. Galantamine potentiated nAChR function to a similar degree at both P15 and P80‐120, although this potentiation was significantly greater in females than in males at each age. Results from this study suggest that distinct factors are involved in each type of receptor modulation, which are differentially altered during postnatal maturation and across biological sex. Future studies will focus on mechanisms by which these factors influence the modulation of α4β2* nAChRs during postnatal maturation.

New insights on the potential effect of progesterone in Covid‐19: Anti‐inflammatory and immunosuppressive effects

“…Moreover, P4 is regarded as an allosteric modulator of the nAchR 16 . An experimental study found that P4 activates central nAchR leading to neuroprotective effects 113 .…”

“…Moreover, P4 is regarded as an allosteric modulator of the nAchR. 16 An experimental study found that P4 activates central nAchR leading to neuroprotective effects. 113 In COVID‐19, SARS‐CoV‐2 binds nAchR leading to dysregulation of the anti‐inflammatory cholinergic system with further augmentation of the release of pro‐inflammatory cytokines.…”

“…In addition, P4 acts as a ligand for progesterone receptor component 1 (PGRMC1), regulating body metabolism, tumor growth, and neuron viability 14 . However, P4 is considered an antagonist for mineralocorticoid receptors (MRs) 15 and sigma receptors with an allosteric modulator of nicotinic acetylcholine receptor (nAchR) 16 . In addition, P4 acts as an antagonist of glucocorticoid receptors (GRs), 17 and P4 metabolites like allopregnanolone and 5α‐dihydro‐progesterone operate as neurosteroids and act as positive allosteric modulators of γ‐aminobutyric acid type A (GABA A ) receptors 18 .…”

“… 14 However, P4 is considered an antagonist for mineralocorticoid receptors (MRs) 15 and sigma receptors with an allosteric modulator of nicotinic acetylcholine receptor (nAchR). 16 In addition, P4 acts as an antagonist of glucocorticoid receptors (GRs), 17 and P4 metabolites like allopregnanolone and 5α‐dihydro‐progesterone operate as neurosteroids and act as positive allosteric modulators of γ‐aminobutyric acid type A (GABA A ) receptors. 18 Likewise, P4 metabolite 5β‐dihydro‐progesterone activates the pregnane X receptor (PXR), which is regarded as xenobiotic and steroid‐sensing nuclear receptors involved in the detoxification of toxic agents from the body 19 (Figure 2 ).…”