Metal Toxicity at the Synapse: Presynaptic, Postsynaptic, and Long-Term Effects

Table 5

Effects of metals on postsynaptic ligand-gated ion channels (↑—activation/upregulation, ↓—inhibition/downregulation).

Target		NMDA	AMPA/kainate	GABA-A
Lead	Effect	(1) ↓ open channel probability		(1) ↓ (35%)
		(2) 60% ↓ in current (reversible)
		(3) >80% block
		(4) ↓
		(5) ↓
		(6) ↓ receptor binding
		(7) ↓
	Conc	(1) 1–10		(1) 1m M
		(2) 50
		(3) 100
		(4) IC50 = 1.52–8.19
		(5) IC50 = 8.78 (in 0 Zn); IC50 = 1.26 (10 Zn) at high site, 94 at low site
		(6) IC50 = 300 (adult); 60 (neonatal)
		(7) IC50 (free) = 0.55
	Ref	(1) [16]		(1) [10]
		(2-3) [14]
		(4) [20]
		(5) [9]
		(6) [12]
		(7) [5]
	Zinc	Effect	(1) ↓ open	(1) ↑	(1) ↓
			channel probability
(2) Channel block			(2) ↓	↓ current in voltage independent, noncompetitive manner
(3) NR2A block			(3) ↑
(4) NR2B block			(4) ↓
(5) ↓			(5) ↑ (16% to kainate, 15% to glu peak and steady state)
(6) ↓ receptor binding (76%)			(6) ↓
(7) ↓			(7) ↑ AMPA response
(8) ↓			(8) ↑ desensitized Kainate responses
			(9) ↓ AMPA and kainate responses
Conc		(1) 1–10 μM	(1) 50	(1) 100 (dose dependent)
		(2) >20	(2) 1 mM	(2) IC50 = 19
		(3) nM	(3) <300
		(4) μM	(4) >500
		(5) High affinity: IC50 = 0.77; low affinity: IC50 = 153	(5) 10
		(6) 1 mM	(6) IC50 = 700
		(7) IC50 (free) = 1.3	(7) EC50 = 30
		(8) IC50 = 42.9	(8) EC50 = 13
			(9) IC50 = 1.2-1.3 mM
		(1-2) [11]	(1-2) [17]	(1) [13]
		Ref	(3) [17, 21]	(3-4) [7, 25]	(2) [10]
(4) [17]			(5-6) [15]
(5) [9]			(7-9) [22]
(6) [12]
(7) [5]
(8) [22]
Magnesium		Effect	(1) ↑ NMDA-R affinity to glycine in all receptors	(1) ↓ (27%)
			(2) ↓ elementary current at +ve potentials(+20 to +80)
	(3) ↑ glycine and voltage-independent and subunit specific
	(4) external channel block, voltage dependent
	Conc	(1) 10 mM	(1) 20 mM
		(2) 10 mM
		(3) 2 mM
		(4) IC50 (−100 mV) = 2–15
	Ref	(1–3) [6]	(1) [15]
		(4) [2]
	Manganese	Effect	(1) ↓ (activity dependent, channel blocker)	(1) ↓ (46%)	(1) Little or no effect
		Conc	(1) Ki = 35.9 (presence of glu and gly); Ki = 157 (no glu nor gly)	(1) 25 mM	(1) 1 mM
Ref		(1) [8]	(1) [15]	(1) [10]
Copper		Effect	(1) ↓	(1) ↓	(1) ↓ (voltage independent)
			(2) ↓ receptor binding (54%)	(2) ↓ kainite-induced current
	(3) ↓ (channel block)		(3) ↓ efficacy of kainate
	(4) ↓
	(5) ↓ voltage independent, noncompetitive
	Conc	(1) ND	(1)
		(2) 1 mM	(2) IC50 = 4.3
		(3) Ki = 195 (no coagonists);	(3) 30
		two sites (9.4, 248) with glu and gly		(1) IC50 = 5
		(4) IC50 = 15
		(5) IC50 (free) = 0.27
	Ref	(1) [17, 23]	(1) [17]	(1) [10]
		(2) [12]	(2-3) [30]
		(3) [8]
		(4) [30]
		(5) [28]
	Cobalt	Effect	(1) ↓	(1) ↓	(1) ↓
				(2) ↓	(2) ↓ (29%)
Conc		(1) 2 mM	(1) 2 mM	(1) 2 mM
			(2) IC50 = 6.1 mM	(2) 1 mM
Ref		(1) [3]	(1) [3]	(1) [3]
			(2) [15]	(2) [10]
Nickel		Effect	(1) NR2A: ↓, NR2B: ↑	(1) ↓ (kainite-induced current)	(1) ↓(20%)
			(2) NR2A ↓ (100% at +ve potentials)	(2) ↓ (glu-induced current)
	(3) NR2B ↓
	(4) NR2B ↑ (voltage independent)
	Conc	(1) 30
		(2) IC50 = 36 at −60 mV and 81 at +40 mV
		(3) IC50 138 at −60 mV and 442 at +40 mV
		(4) 3
			(1) IC50 = 420	(1) 1 mM
			(2) IC50 = 2.6 mM
	Ref	(1) [16]	(1-2) [15]	(1) [10]
		(2–4) [21]
	Mercuric chloride	Effect			(1) ↑ 130%
					(2) ↑ (270%)
Conc				(1) 1
				(2) 100
Ref				(1) [1]
				(2) [19]
Methyl mercury		Effect	(1) ↓ receptor binding		(1) ↓ amplitude to 82.4%
		Conc	(1) IC50 = 0.95 (neonatal); 70 (adult)		(1) 100
	Ref	(1) [12]		(1) [55]
	Cadmium	Effect	(1) ↓ receptor binding (58%)	(1) ↑ (kainate to 108% and QA to 115%)	(1) ↓ (18%)
			(2) ↓ (39% of control)	(2) ↓ (kainate to 79% and QA to 60%)
		(3) ↓ (4% of control)
Conc		(1) 1 mM	(1) 50	(1) 1 mM
		(2) 50	(2) 1 mM
		(3) 1 mM
		(1) [12]	(1-2) [18]	(1) [10]
Ref		(2-3) [18]
Lanthanide		Effect	(1) ↓ NMDA response in a voltage-independent manner	(1) ↑	(1) ↑ (300% max) and ↑ as the potential more −ve
			(2) ↓
	Conc	(1) IC50 = 2	(1) 1–100	(1) EC50 = 231
			(2) >100
	Ref	(1) [27]	(1-2) [27]	(1) [10]
	Trimethyl-tin (TMT)	Effect	(1) ↓ (35%) reversible	(1) ↓ (20%) irreversible	(1) ↓ (30%) irreversible
		Conc	(1) 100	(1) 100	(1) 100
Ref		(1) [4]	(1) [4]	(1) [4]