Chapter 34 - Ion Channels Regulated by Direct Binding of Cyclic Nucleotides

Abstract

Certain ion channels in the plasma membrane are regulated by the binding of cyclic nucleotides (cAMP or cGMP) on the cytoplasmic side. These channels enable a cell to give a direct electrical response to its own internal cyclic nucleotide messengers, in the same way that a neuron responds to external neurotransmitters acting on traditional ionotropic receptors. This chapter highlights some unusual functional aspects of the 6TM-CNB channels and points out some recent achievements and remaining challenges in understanding their mechanistic basis. Cyclic nucleotide gated (CNG) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels can be expressed heterologously, and retain activity in membrane patches that have been excised from the cell in an inside-out patch clamp configuration, whereas many other 6TM-CNB channels lose activity quickly after patch excision (“rundown”). CNG channels are directly opened by cyclic nucleotide at any voltage; HCN channels are activated by membrane hyperpolarization. For both CNG and HCN channels, the coupling of cyclic nucleotide binding to gate-opening is allosteric rather than obligatory. CNG channels can open “spontaneously” with a low but non-zero open probability. HCN channels can reach the open state through hyperpolarization. Differential agonist binding requires that the receptor domain change its structure during ligand activation, whether at the level of tertiary structure or quaternary structure. The receptor domain's structural change must be coupled to movement of a “gate” structure in the pore domain. Finally, the voltage-sensing domain forms yet another allosteric protein that is coupled to the pore domain.