Modulation of Channel Activity

Increases in [Ca2+]c activate the Ca2+-dependent K+ channel, either large (BK) or small (SK) conductance, (Kca2+),7,105,124 limiting the firing frequency of repetitive action potentials. In hippocampal neurons, activation of BK channels underlies the falling phase of the action potential and generation of the fast afterhyperpolarization. In contrast, SK channel activation underlies generation of the slow afterhyperpolarization after a burst of action potentials. The source of Ca2+ for BK channel activation is probably N-type channels, which activate the BK channel only, with opening of the two channel types being nearly coincident,77 suggesting that the N-type Ca2+ and BK channels are functionally very close. Direct coupling of NMDA receptors to BK-type Ca2+-activated K+ channels has also been reported in the inhibitory granule cells of rat olfactory bulb.60 The slow afterhyperpolarization is blocked by dihydropyridine antagonists, indicating that L-type Ca2+ channels provide the Ca2+ for activation of SK channels. L-type channels activate SK only and the delay between the opening of L-type channel and SK channels indicates that these two types of channels are 50-150 nm apart.7 Thus, there exists an absolute segregation of coupling between channels, indicating the functional importance of submembrane Ca2+ micro-domains. Some of these effects on K+ channels may be mediated by Ca2+-binding signal proteins.88

Long-Term Changes of Ca2+-Influx via Memory-Specific K+ Channel Regulation

Memory-related Ca2+ signals are decoded through altered operation of membrane channels, including K+ channels. K+ channels play an important role in memory formation (for review, see Vernon and Giese in this book). The phosphorylation and dephosphorylation of the Shaker-related fast-inactivating Kv1.4 is regulated by [Ca2+]c.134 CaMKlI phosphorylation of an amino-terminal residue of Kv1.4 leads to N-type inactivated states. Dephosphorylation of this residue induces a fast inactivating mode. Associate learning paradigms in a variety of species have now been closely correlated with long-term changes of voltage-dependent K+ channels, particularly those in the Shaker family and those that are Ca2+-dependent. Voltage-dependent Ia channels were shown to occur in the single identified type B cells of the Mollusk Hermissenda only when the animal acquired a Pavlovian- conditioned response.4 The same type of K+ channel change was demonstrated to last even one month in duration in the post-synaptic dendrites of the cerebellar HVI Purkinje cells only when a rabbit had acquired and retained a Pavlovian-conditioned eye-blink response.1 3,104 Similar changes of a post-synaptic K+ channels were found in the rabbit hippocampus and were correlated with enhanced EPSP summa-tion.25,74

These correlated learning-specific changes were found to bear a causal relationship to the acquisition of associative learning using an antisense strategy. Antisense "knockdown" of Shaker postsynaptic Kv1.1 K+ channels in the hippocampus eliminated retention of a spatial maze learning task81 while "knockdown" of the presynaptic Kv1.4 K+ channel did not alter learning or memory of the task.82

Such memory-specific reductions of voltage-dependent as well as GABA-mediated K+ conductance will enhance synaptic depolarization of post-synaptic membranes and thereby enhance opening of VOCC. In this way, learning-specific reduction of K+ conductance will increase Ca2+ influx across the plasma membrane. During learning and even retention, enhanced voltage-dependent Ca2+ influx can combine with learning-specific enhancement of intracellular Ca2+ release via the RyR and IP3R to cause further activation of downstream Ca2+-dependent molecular cascades.

Figure 2. Model of Ca2+ binding by C2 motifs of synaptotagmin I. The Ca2+ binding residues are in loop 1 and loop 3. Solid circles represent residues shown in single-letter amino acid code and identified by number (adapted from refs. 39 and 121).

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