Calmodulin plays a dominant role in determining neurotransmitter regulation of neuronal adenylate cyclase

Abstract

Ca²⁺, through the mediation of calmodulin, stimulates the activity of brain adenylate cyclase. The growing awareness that fluctuating Ca²⁺, concentrations play a major role in intracellular signalling prompted the present study, which aimed to investigate the implications for neurotransmitter (receptor) regulation of enzymatic activity of this calmodulin regulation. The role of Ca²⁺/calmodulin in regulating neurotransmitter-mediated inhibition and stimulation was assessed in a number of rat brain areas. Ca²⁺/calmodulin stimulated adenylate cyclase activity in EGTA-washed plasma preparations from each region studied—from 1.3-fold (in striatum) to 3.4-fold (in cerebral cortex). The fold-stimulation produced by Ca²⁺/calmodulin was decreased in the presence of GTP, forskolin, or Mn²⁺. In EGTA-washed membranes, receptor-mediated inhibition of adenylate cyclase was strictly dependent upon Ca²⁺/calmodulin stimulation in all regions, except striatum. A requirement for Mg²⁺ in combination with Ca²⁺/calmodulin to observe neurotransmitter-mediated inhibition was also observed. In contrast, receptor-mediated stimulation of activity was much greater in the absence of Ca²⁺/calmodulin. The findings demonstrate that ambient Ca²⁺ concentrations, in concert with endogenous calmodulin, may play a central role in dictating whether inhibition or stimulation of adenylate cyclase by neurotransmitters may proceed.