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  • Lamina II SG spinal cord neurons play an important role

    2021-09-22

    Lamina II (SG) spinal cord neurons play an important role in regulating nociceptive input from the periphery [20,21]. Moreover, lamina II neurons are concentrated with glycinergic or GABAergic inhibitory interneurons. Therefore, it is possible that β-alanine might modulate nociceptive transmission in the spinal cord. This idea is supported by our previous report that taurine (β-amino acid), a structural analog of β-alanine, activates glycine and GABAA receptors in rat SG neurons [22]. In the present study, we aimed to examine whether β-alanine affects SG neurons by using whole-cell patch-clamp technique.
    Materials and methods
    Results
    Discussion Several lines of evidence suggest that β-alanine pharmacologically activates glycine and GABAA receptors in the CNS [1,7,8]. However, function of β-alanine on spinal dorsal horn neurons has not been examined previously. In this study, we investigated bath applied β-alanine-induced currents in SG neurons from adult rat spinal cord slices using whole-cell patch-clamp. First, we demonstrated that β-alanine induced an outward current in SG neurons, and the amplitude of this current increased in a concentration dependent manner. Second, β-alanine opened Cl− Annexin V-Cy3 Apoptosis Kit Plus receptor on postsynaptic SG neurons and determined the ion channel responsible for membrane currents. Finally, we examined the pharmacological properties of β-alanine-induced currents and found that β-alanine activated glycine, but not GABAA, receptors. These results indicate that β-alanine activates the strychnine-sensitive glycine receptors in SG neurons, and may act as a functional neurotransmitter in the spinal dorsal horn. Multiple CNS receptors respond to endogenous β-alanine, which is not surprisingly because β-alanine is structurally intermediate between the main inhibitory neurotransmitters, glycine (α-amino acid) and GABA (γ-amino acid). β-alanine has some recognized receptor sites: the GABAA receptor site; glycine receptor site (strychnine sensitive); and glycine co-agonist site on the NMDA complex (strychnine-insensitive) [9,10]. Other studies have suggested that an additional unique β-alanine receptor, MrgD (TGR7), acts as a specific receptor for β-alanine [23]. However, our results suggest that the reversal potential was close to the theoretical Cl− equilibrium potential. Moreover, β-alanine-induced currents were completely blocked by a glycine, but not GABAA, receptor. These results indicate that β-alanine acts on a strychnine-sensitive site of the glycine receptor to open Cl− channels in SG neurons and decreases the excitability of the membrane, resulting in hyperpolarization. Previous studies have demonstrated that β-alanine activates glycine and GABAA receptors in the CNS [[24], [25], [26], [27]]; however, the present study demonstrated that β-alanine activates glycine receptors selectively in SG neurons of the spinal dorsal horn. The difference in GABAA receptor affinity for β-alanine at different locations in the CNS has not been explained satisfactorily, but may be due to the different composition of GABAA receptors. GABAA receptors are composed of five subunits, of which 19 subunits have been cloned: α1-6, β1-3, γ1-3, δ, ε, θ, π and ρ1-3 [28]. The same GABAA receptors can have different subunit compositions; therefore, the affinity for ligands and receptor properties change [28]. It has been reported that the most abundantly expressed GABAA receptors in the CNS are composed of two α1, two β, and one γ2 subunit [29], whereas in the spinal cord of the dorsal horn, α2 subunits are predominant [30]. Moreover, Hadley et al. reported that β-alanine activates GABAA receptors containing α6, β2, and δ subunits with high potency [31]. These findings may contribute to the different sensitivities of β-alanine for GABAA receptors in the brain and spinal cord. Subunit composition and distribution of GABAA receptors that interact with β-alanine require further detailed studies.