A recent study identified Nipsnap1 as an auxiliary protein inhibiting TRPV6 ion channel activity. Based upon this finding, we investigated the role of Nipsnap1, and the closely related Nipsnap2, in Ca(2+) channel regulation. Here, we find that overexpression of Nipsnap2 caused a 45% increase in currents though L-type Ca(2+) channels in a neuronal cell line, while siRNA knockdown of Nipsnap2 greatly reduced L-type currents. The increased influx through L-type Ca(2+) channels due to Nipsnap2 overexpression led to increased phosphorylation of the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) along with enhanced expression of several transcription factors and CREB target genes. These experiments highlight a novel role of Nipsnap2 in transcriptional regulation via L-type Ca(2+) channels.