L-type voltage-gated Ca2+ channels (LTCC) have long been considered as crucial regulators of neuronal excitability. Thereby, the coupling of LTCC-mediated Ca2+ influx and Ca2+-dependent channels including KCa channels and non-specific cation channels is thought to mediate depolarizing and hyperpolarizing afterpotentials, respectively. However, the mechanisms of interaction of L-type, KCa and CAN channels remained scarcely known. This work focuses on the activation of LTCCs and their effects on neuronal excitation in respect to Ca2+-dependent potassium and CAN conductances. Using primary hippocampal neurons in culture, current pulse injections were applied in the presence of tetrodotoxin (TTX) for stepwise depolarization. The activation of LTCCs was modulated using the dihydropyridines BayK 8644 (agonist) and isradipine (antagonist). The variation of current pulse length and strength indicated that LTCC activation tends to enhance weak depolarizing stimuli and counteract stronger depolarization. Moreover, both effect modes seem to involve the same Ca2+-dependent channels that mediate depolarizing (ADP) and hyperpolarizing (AHP) afterpotentials. Thereby, ADPs were activated at weaker depolarizing pulses or shorter current injections than AHPs. Furthermore, to evaluate the regulation of neuronal excitability in normal dicharge activity, experiments were also done in the absence of TTX. Depending on the initial burst duration, activation of L-type Ca2+ channels prolonged or shortened the mean burst length. Moreover, brief provoked and unprovoked electical events were augmented. Thus, the modulation of membrane excitability via LTCCs involves the concomitant activation of both excitatory and inhibitory Ca2+-activated conductances. Hence, the overall enhancing or dampening effect of LTCC activation on neuronal excitability depends on the relative abundance of the respective coupling channel as well as on the stimulus intensity. This excitation-dependent activation of L-type Ca2+ channel coupled conductances may have important implications for the usability of LTCC modulators in the treatment of various forms of abnormal neuronal electrical activities.