Molecular Determinants of APs

The membrane conductances that underlie the AP reflect the activities of several members of the voltage-gated ion channel (VGIC) superfamily of membrane proteins (Figure 2). VGICs respond to membrane depolarization with conformational changes that reveal an ion-selective pore through which specific ions pass in a diffusion-limited manner. Members of the VGIC superfamily have a positively charged transmembrane domain known as the S4 helix, the structure of which depends upon the transmembrane voltage (for review, see Gandhi and Isacoff, 2002).

Pore

Pore

gated potassium channel a-subunit in the membrane is shown. The S4 transmembrane domain, thought to be critical for voltage-dependent gating, is indicated. Similar S4 domains are also found in voltage-gated sodium and potassium channels and are a hallmark of the VGIC superfamily. 'N' and 'C' indicate the amino- and carboxyl-termini, respectively. Reprinted by permission from Macmillan Publishers Ltd: Nature(Yellen, G. 2002. The voltage-gated potassium channels and their relatives. Nature 419, 35-42), copyright (2002).

gated potassium channel a-subunit in the membrane is shown. The S4 transmembrane domain, thought to be critical for voltage-dependent gating, is indicated. Similar S4 domains are also found in voltage-gated sodium and potassium channels and are a hallmark of the VGIC superfamily. 'N' and 'C' indicate the amino- and carboxyl-termini, respectively. Reprinted by permission from Macmillan Publishers Ltd: Nature(Yellen, G. 2002. The voltage-gated potassium channels and their relatives. Nature 419, 35-42), copyright (2002).

VGICs exist in species throughout the animal and plant kingdoms, including prokaryotes, protozoa, yeast, vascular plants, coelenterates, nematodes, arthropods, mollusks, teleosts, and tetrapods (for review, see Hille, 2001). Not surprisingly, APs have been recorded from cells in a range of species spanning the animal and plant kingdoms (for review, see Hille, 2001). During the last 20 years, many genes and transcripts for a large variety of VGIC proteins have been cloned and characterized. Noda et al. (1984) reported the cloning of a voltage-gated sodium channel from the electric organ of the electric eel, Electrophorus electricus. The cloning of a voltage-gated calcium channel from rabbit skeletal muscle followed in 1987 (Tanabe et al., 1987). That same year, several groups reported cloning of the Drosophila Shaker potassium channel gene (Kamb et al., 1987; Papazian et al., 1987; Pongs et al., 1988; Schwartz et al., 1988). Comparisons of the primary sequences of cloned VGIC genes have revealed a high degree of conservation among species that are distantly related (for review, see Jan and Jan, 1990; Coetzee et al., 1999; Moreno-Davila, 1999; Goldin, 2001; Yu and Catterall, 2003). Such findings suggest that the key structural and functional properties of VGICs have been conserved during evolution.

Molecular cloning has revealed an unexpectedly large number of VGIC genes, many more than might have been expected on the basis of physiological recording. Current research seeks to identify the specific roles of the many VGIC genes that have been identified. A common finding has been that VGIC gene subfamilies may have multiple members in vertebrates (e.g., Kv1 family: Kv1.1-Kv1.9; Nav1 family: Nav1.1-Nav1.9, respectively) but only a single ortho-logous gene in invertebrates (e.g., Drosophila Shaker; Drosophila para, respectively).

Phylogenetic analyses suggest that VGICs evolved from an ancestral voltage-gated potassium channel (for review, see Hille, 2001; Yu et al., 2005). Further, voltage-gated calcium, but not sodium, channels have been detected in unicellular organisms (DeHertogh et al., 2002). APs recorded from species lacking voltage-gated sodium channels rely upon voltage-gated calcium channels for their initiation and typically are much longer-lasting events that signal via changes in intracellular calcium ion concentrations.

Phylogenetic analyses indicate that voltage-gated sodium channels evolved later than did voltage-gated potassium and calcium channels. Voltage-gated sodium channel function also enlisted a sodium pump that establishes a transmembrane sodium gradient (Stein, 2002). Voltage-gated sodium channels underlie the ability of the AP to be a rapid spike, occur in bursts, and propagate rapidly. Thus, the later evolution of voltage-gated sodium channels introduced important changes into the AP waveform, allowing it to be a rapid spike. Further, voltage-gated sodium channels allow APs to occur repetitively at high frequencies. Thus, voltage-gated sodium channels significantly expanded the roles that APs can play in information processing and behavior.

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