Abstract

Cyclic nucleotide-gated (CNG) channels conduct Na⁺, K⁺ and Ca²⁺ currents under the control of cGMP and cAMP. Activation of CNG channels leads to depolarization of the membrane voltage and to a concomitant increase of the cytosolic Ca²⁺ concentration. Several polypeptides were identified that constitute principal and modulatory subunits of CNG channels in both neurons and non-excitable cells, co-assembling to form a variety of heteromeric proteins with distinct biophysical properties. Since the contribution of each channel type to Ca²⁺ signaling depends on its specific Ca²⁺ conductance, it is necessary to analyze Ca²⁺ permeation for each individual channel type. We have analyzed Ca²⁺ permeation in all principal subunits of vertebrates and for a principal subunit from Drosophila melanogaster. We measured the fractional Ca²⁺ current over the physiological range of Ca²⁺ concentrations and found that Ca²⁺ permeation is determined by subunit composition and modulated by membrane voltage and extracellular pH. Ca²⁺ permeation is controlled by the Ca²⁺-binding affinity of the intrapore cation-binding site, which varies profoundly between members of the CNG channel family, and gives rise to a surprising diversity in the ability to generate Ca²⁺ signals.