Potassium channel interacting proteins (KChIP) are Ca(2+)-binding proteins that originally were identified as auxiliary subunits for K(V)4 channels. K(V)4 channels encode the voltage gated A-current (I(A)) in neuronal tissue and the fast, transient outward current (I(to,f)) in cardiac tissue. Recently, we have reported that KChIP2 functionally modulates the cardiac Ca(V)1.2-governed L-type Ca(2+) current (I(Ca,L)) through a direct interaction between KChIP2 and the amino-terminus of Ca(V)1.2. Here, we show that KChIP2 and Ca(V)1.2 co-immunoprecipitate enhancing the biochemical support for our previous finding. Using gene-chip and real-time PCR techniques, we find that KChIP2(-/-) mice have an increased transcriptional activity of the calcium channel beta(2) subunit, CACNB2, whereas the expression of Ca(V)1.2 is preserved. Although I(to,f) is absent and I(Ca,L) is decreased in myocytes from KChIP2(-/-) mice, the action potential morphology is not altered. Furthermore, we show that the ventricular effective refractory period (VERP) is comparable in wild-type (53 +/- 5 ms) and KChIP2(-/-) mice (48 +/- 3 ms; p > 0.05). In summary, our findings document a novel function of KChIP2 and expand our insights into the in vivo modulation of cardiac ion currents.