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The myogenic cardiac pacemaker of Drosophila melanogaster responds to a range of neurotransmitters and hormones by adjusting heart rate. These cardioactive substances ultimately affect the activity of ion channels comprising the pacemaker. We report here work utilizing genetic variants and pharmacological tools to explore a subset of possible mechanisms for this cellular signaling, specifically: receptors, cAMP, cGMP, G proteins, and calcium. We found that alpha(1) adrenergic and 5-hydroxytryptamine(2) (5-HT(2)) receptors are critical components of mediating modulation of heart rate. There was no evidence that the cAMP system is part of the modulatory mechanism. cGMP is likely to be integral to one active pathway, as non-hydrolyzable forms of this cyclic nucleotide increase heart rate, and flies bearing the mutation sitter, a recessive allele of the foraging gene, which encodes a cGMP-dependent kinase, have tachycardia. Heart rhythm is affected by pertussis toxin and by agonists and antagonists of both alpha(1) adrenergic and 5-HT(2) receptors; this suggests involvement of two different types of G proteins. The l(4)16/ciD line, containing a mutation in CaM kinase II, eliminates pacemaker responsiveness to serotonin but is without effect on norepinephrine sensitivity. This result is the same as that for the CaM kinase II enzyme inhibitor KN-93. This work establishes a framework for further investigations into the control of the cardiac pacemaker, and expands the applicability of the Drosophila heart model.

Brain development requires precise regulation of axon outgrowth, guidance and termination by multiple signaling and adhesion molecules. How the expression of these neurodevelopmental regulators is transcriptionally controlled is poorly understood. The Caenorhabditis elegans SMD motor neurons terminate axon outgrowth upon sexual maturity and partially retract their axons during early adulthood. Here we show that C-Terminal Binding Protein-1 (CTBP-1), a transcriptional corepressor, is required for correct SMD axonal development. Loss of CTBP-1 causes multiple defects in SMD axon development: premature outgrowth, defective guidance, delayed termination and absence of retraction. CTBP-1 controls SMD axon guidance by repressing the expression of SAX-7 - a L1 cell adhesion molecule (L1CAM). CTBP-1-regulated repression is crucial as deregulated SAX-7/L1CAM causes severely aberrant SMD axons. We found that axonal defects caused by deregulated SAX-7/L1CAM are dependent on a distinct L1CAM, called LAD-2, which itself plays a parallel role in SMD axon guidance. Our results reveal that harmonization of L1CAM expression controls the development and maturation of a single neuron.

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