1. Introduction 374

2. Metals in biology 378

3. The targets: structure and function of ion channels 380

4. General effects of metal ions on channels 382

4.1 Three types of general effect 382

4.2 The main regulators 383

5. Effects on gating: mechanisms and models 384

5.1 Screening surface charges (Mechanism A) 387

5.1.1 The classical approach 387

5.1.1.1 Applying the Grahame equation 388

5.1.2 A one-site approach 391

5.2 Binding and electrostatically modifying the voltage sensor (Mechanism B) 391

5.2.1 The classical model 391

5.2.1.1 The classical model as state diagram – introducing basic channel kinetics 392

5.2.2 A one-site approach 395

5.2.2.1 Explaining state-dependent binding – a simple electrostatic mechanism 395

5.2.2.2 The relation between models assuming binding to smeared and to discrete charges 396

5.2.2.3 The special case of Zn2+ – no binding in the open state 396

5.2.2.4 Opposing effects of Cd2+ on hyperpolarization-activated channels 398

5.3 Binding and interacting non-electrostatically with the voltage sensor (Mechanism C) 398

5.3.1 Combining mechanical slowing of opening and closing with electrostatic modification of voltage sensor 400

5.4 Binding to the pore – a special case of one-site binding models (Mechanism D) 400

5.4.1 Voltage-dependent pore-block – adding extra gating 401

5.4.2 Coupling pore block to gating 402

5.4.2.1 The basic model again 402

5.4.2.2 A special case – Ca2+ as necessary cofactor for closing 403

5.4.2.3 Expanding the basic model – Ca2+ affecting a voltage-independent step 404

5.5 Summing up 405

6. Quantifying the action: comparing the metal ions 407

6.1 Steady-state parameters are equally shifted 407

6.2 Different metal ions cause different shifts 408

6.3 Different metal ions slow gating differently 410

6.4 Block of ion channels 412

7. Locating the sites of action 412

7.1 Fixed surface charges involved in screening 413

7.2 Binding sites 413

7.2.1 Group 2 ions 414

7.2.2 Group 12 ions 414

8. Conclusions and perspectives 415

9. Appendix 416

10. Acknowledgements 418

11. References 418

Metal ions affect ion channels either by blocking the current or by modifying the gating. In the present review we analyse the effects on the gating of voltage-gated channels. We show that the effects can be understood in terms of three main mechanisms. Mechanism A assumes screening of fixed surface charges. Mechanism B assumes binding to fixed charges and an associated electrostatic modification of the voltage sensor. Mechanism C assumes binding and an associated non-electrostatic modification of the gating. To quantify the non-electrostatic effect we introduced a slowing factor, A. A fourth mechanism (D) is binding to the pore with a consequent pore block, and could be a special case of Mechanisms B or C. A further classification considers whether the metal ion affects a single site or multiple sites. Analysing the properties of these mechanisms and the vast number of studies of metal ion effects on different voltage-gated ion channels we conclude that group 2 ions mainly affect channels by classical screening (a version of Mechanism A). The transition metals and the Zn group ions mainly bind to the channel and electrostatically modify the gating (Mechanism B), causing larger shifts of the steady-state parameters than the group 2 ions, but also different shifts of activation and deactivation curves. The lanthanides mainly bind to the channel and both electrostatically and non-electrostatically modify the gating (Mechanisms B and C). With the exception of the ether-à-go-go-like channels, most channel types show remarkably similar ion-specific sensitivities.