Neurons expand, sustain or prune their dendritic trees during ontogenesis [Cline, H.T. (2001). Dendritic arbor development and synaptogenesis. Curr. Opin. Neurobiol. 11, 118-126; Wong, W.T. and Wong, R.O.L. (2000) Rapid dendritic movements during synapse formation and rearrangement. Curr. Opin. Neurobiol. 10, 118-124] which critically depends on neuronal activity [Wong, W.T., Faulkner-Jones, B.E., Sanes, J.R. and Wong, R.O.L. (2000) Rapid dendritic remodeling in the developing retina: dependence on neurotransmission and reciprocal regulation by Rac and Rho. J. Neurosci. 20, 5024-5036; Li, Z., Van Aelst, L. and Cline, H.T. (2000) Rho GTPases regulate distinct aspects of dendritic arbor growth in Xenopus central neurons in vivo. Nat. Neurosci. 3, 217-225; Wong, W.T. and Wong, R.O.L. (2001) Changing specificity of neurotransmitter regulation of rapid dendritic remodeling during synaptogenesis. Nat. Neurosci. 4, 351-352.] and sub-cellular Ca(2+) signals [Lohmann, C., Myhr, K.L. and Wong, R.O. (2002) Transmitter-evoked local calcium release stabilizes developing dendrites, Nature 418, 177-181.]. The role of synaptic clustering proteins connecting both processes is unclear. Here, we show that expression levels of Vesl-1/Homer 1 isoforms critically control properties of Ca(2+) release from intracellular stores and dendritic morphology of CNS neurons. Vesl-1L/Homer 1c, an isoform with a functional WH1 and coiled-coil domain, but not isoforms missing these features were capable of potentiating intracellular calcium signaling activity indicating that such regulatory interactions function as a general paradigm in cellular differentiation and are subject to changes in expression levels of Vesl/Homer isoforms.