The cellular prion protein (PrP^c) is a highly conserved cell surface glycoprotein expressed in the Central Nervous System. Its conformationally modified isoform, PrPsc, is responsible for the Transmissible Spongiform Encephalopathies or prion diseases. In the last years, multiple and diverse functions of PrP^c have been reported in neural tissues as neuroprotection, neuronal differentiation and memory consolidation. In order to elucidate the physiological functions of PrP^c, our group identified and characterized the interaction between PrP^c and the extracellular matrix molecule laminin (LN). The binding region is located at the carboxi-terminal of the g-1 LN chain (residues 1575-RNIAEIIKDI-1584). In this work we reported role of Ca²⁺ in PrP^c signaling elicited by g-1 peptide binding to hippocampal neurons of wild-type (Prnp^+/+) and Prpc-gene ablated (Prnp^0/0) mice. We showed that this peptide was able to induce both the percentage of Prnp^+/+ neurons extending neuritis and in the number of neurites/cell. In Prnp^+/+ neurons loaded with an intracellular Ca²⁺ probe, Fluo- 3M,  g-1 induced intracellular Ca²⁺ increase by endoplasmic reticulum mobilization and by extracellular medium influx. Remarkable, neuritogenesis and Ca⁺² signaling were dependent on the KDI residues present in the g-1 chain peptide. Conversely, g-1 chain peptide presented no effect in neuritogenesis and Ca⁺² signaling in Prnp^0/0 neurons.  The role of Ca²⁺ signaling in the peptide-mediated neuritogenesis was evaluated in hippocampal neurons after treatment with PLC or PKC inhibitors. These drugs were able to completely block neurite extension. Thus, our data suggest that neuritogenesis induced by PrP^c engagement to the KDI domain at the g-1 chain peptide, is dependent on intracellular Ca²⁺ signaling.