Glutamate is the principal neurotransmitter in the brain, mediating fast synaptic transmission through AMPA-type glutamate receptors (AMPARs). Four receptor subunits (GluR1-4) form AMPA channels, the properties of which differ depending on RNA editing, alternative splicing and subunit composition. Furthermore, AMPA receptor properties critically depend on the presence of AMPAR auxiliary proteins. These transmembrane AMPAR regulatory proteins (TARPs) control both AMPA receptor trafficking and gating (Nicoll et al., 2006). We have recently shown that the prototypical TARP, stargazin (γ-2), increases single channel conductance of Ca2+-permeable AMPARs (CP-AMPARs). Moreover, it attenuates block of CP-AMPARs by intracellular polyamines, resulting in a decreased inward rectification of the current-voltage (I-V) relationship (Soto et al., 2007). Five TARPs have been identified (γ-2, -3, -4, -7 and -8). Here we describe that all TARP family members modify basic properties of CP-AMPAR channels. We used a piezoelectric controller to apply brief pulses (100ms) of glutamate (10mM) to outside-out patches from tsA-201 cells transiently transfected with GluR4 subunits and TARPs. Non-stationary noise analysis of GluR4 responses yielded a weighted-mean single-channel conductance of 17.8 ± 1.5pS (n=4). This conductance was increased by approximately 50% when GluR4 was coexpressed with the various different TARPs (e.g. GluR4 + γ-8, 34.1 ± 4.5pS; n=4); similar changes were obtained for all TARPs tested (P <0.01 for all vs control). Furthermore, all TARPs slowed the desensitization kinetics of AMPARs, with the exception of the most recently described TARP family member γ-7 (GluR4 τ = 3.9 ± 0.4ms, n = 4; GluR4 + γ-7, τ = 3.6 ± 0.5ms n=3); γ-4 and -8 gave the largest change in desensitization kinetics (τ = 9.31 ± 1.9ms n=5 and 9.69 ± 3.56ms n=4, respectively). Furthermore, all TARPs decreased spermine sensitivity of GluR4, altering the I-V relationship, although the extent of the decrease varied between the TARPs, with γ-3 causing the greatest reduction in rectification (RI (+60/-80): 0.02 ± 0.01, n=5 for control vs. 0.34 ± 0.02, n=4 for γ-3 (P<0.001). Our experiments demonstrate that, in common with stargazin, other TARPs modify the biophysical properties of CP-AMPARs, and that the extent of the change varies between TARPs. As the type of TARPs expressed varies between brain areas (Tomita et al., 2003), our results suggest that CP-AMPARs may be differentially modulated in different cell types.