Spontaneous hyperpolarizations (SHPs) or spontaneous miniature outward currents (SMOCs) that are generated by the activation of small conductance, calcium dependent potassium channels (SK channels) through ryanodine receptor-mediated calcium release from intracellular stores are regulated by and regulate themselves intracellular calcium. Muscarine is known to increase intracellular calcium concentration. Gramicidin perforated patch recording revealed that muscarinic agonists (carbachol or muscarine, 10 mM) increased the frequency and duration of SMOCs in conjunction with inducing an inward current. SMOCs preceded the activation of discharge. SMOCs delayed and dampened discharge, but did not prevent activation of discharge. In neurons discharging at relatively high frequency, muscarine did not activate SK channels. Despite the presence of SK channels, therefore, muscarine can induce intracellular calcium increases through the activation of ryanodine receptors and of voltage dependent calcium channels to initiate multiple cellular functions. As an example, depolarization induced suppression of inhibition that can be blocked by endocannabinoid CB1 receptor antagonists is enhanced by muscarinic receptor activation. -Supported by the DFG-