Evidence for two distinct Mg2+ binding sites in Gsα and Giα1 proteins

Inhibition of specific adenylyl cyclase isoforms by lithium and carbamazepine, but not valproate, may be related to their antidepressant effect

“…Catalytic activity of all AC isoforms depends on the presence of Mg 2+ ions (49). While there are two Mg 2+ ‐binding sites on AC, there are also two additional Mg 2+ ‐binding sites on G‐proteins (50). The ability of Li to inhibit both directly stimulated AC (by FSK) and AC which is activated via the D1 receptor stimulation may suggest that Li interacts directly with the enzyme as well as with the G‐protein Mg 2+ ‐binding sites.…”

Lithium – therapeutic tool endowed with multiple beneficiary effects caused by multiple mechanisms

“…It has been proposed that Li + , a metal ion with an ionic radius similar to that of Mg 2+ (Malarkey et al 2008), can compete with Mg 2+ for low affinity Mg 2+ -binding sites in trimeric Gα subunits (Avissar et al 1988, Mota de Freitas et al 2006. Several of the seminal G i 1α protein crystallographic experiments that showed one Mg 2+ --binding site were conducted in the presence of very high (up to 2 M) Li + concentrations (Coleman et al 1994a, 1994b, Coleman and Sprang 1998, or were modeled on structures obtained in the presence of very high Li + concentrations .…”

“…As the latter effect is due to a nucleotide-dependent functional and physical uncoupling of the receptor from G protein, it has been suggested that magnesium cations enhance agonist binding by stabilization of ternary, highaffinity complex H-R-G (complex hormone-receptor-G protein) which is necessary intermediate for hormonal stimulation of effector enzymes as well as guanine nucleotide-dependent transition of receptor from the high to low-affinity state (Bird and Maguire 1978, Tsai and Lefkowitz 1978, Williams et al 1978. It was suggested that lithium interaction with G proteins may proceed as direct competition with magnesium ions bound to the low-affinity Mg2+-sites in Gα subunits (Malarkey et al 2008). Mg2+-binding is known to be essential for agoniststimulated GDP-GTP exchange reaction proceeding in guanine-nucleotide binding domain of Gα subunits, namely, for the fast change of Gα-GTP conformation (Gilman 1987, Higashijima et al 1987a, 1987b, 1987c.…”