α1ESubunits Form the Pore of Three Cerebellar R-Type Calcium Channels with Different Pharmacological and Permeation Properties

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Abstract
R-type Ca2+channels cooperate with P/Q- and N-type channels to control neurotransmitter release at central synapses. The leading candidate as pore-forming subunit of R-type channels is the α1Esubunit. However, R-type Ca2+currents with permeation and/or pharmacological properties different from those of recombinant Ca2+channels containing α1Esubunits have been described, and therefore the molecular nature of R-type Ca2+channels remains not completely settled. Here, we show that the R-type Ca2+current of rat cerebellar granule cells consists of two components inhibited with different affinity by the α1Eselective antagonist SNX482 (IC50values of 6 and 81 nm) and a third component resistant to SNX482. The SNX482-sensitive R-type current shows the unique permeation properties of recombinant α1Echannels; it is larger with Ca2+than with Ba2+as charge carrier, and it is highly sensitive to Ni2+block and has a voltage-dependence of activation consistent with that of G2 channels with unitary conductance of 15 pS. On the other hand, the SNX482-resistant R-type current shows permeation properties similar to those of recombinant α1Aand α1Bchannels; it is larger with Ba2+than with Ca2+as charge carrier,and it has a low sensitivity to Ni2+block and a voltage-dependence of activation consistent with that of G3 channels with unitary conductance of 20 pS. Gene-specific knock-down by antisense oligonucleotides demonstrates that the different cerebellar R-type channels are all encoded by the α1Egene, suggesting the existence of α1Eisoforms with different pore properties.