Nongenomic effects of aldosterone may also be mediated through steroid metabolites. Tetrahydro-derivatives (A-ring reduced forms) of aldosterone elicit sodium appetite ( 16 ) ( 17 ). Injection of aldosterone, deoxycorticosterone (DOCA), or tetrahydro-aldosterone into the medial amygdala rapidly elicits sodium intake that is not affected by prior application of antisense oligonucleotides or antagonists targeting MR ( 17 ). Rather, salt appetite induced by tetrahydro-aldosterone is inhibited by GABA receptor antagonists Ro15-04513 or Ro15-1788, but mimicked by GABA agonist flunitrazepam ( 16, 17 ). Taken together, these studies suggest that the rapid arousal of salt appetite may be a result of the local conversion of aldosterone to its tetrahydroderivative, which in turn activates GABA A receptors.
It is now understood that steroids can act on the cell membrane to bring about various second messenger effects. These second messenger pathways involve kinase pathways driven by classical receptors (MAPk, ERK, MEK, etc), as well as cyclic AMP, lipase and other kinase pathways (PI3K, PKA, PKC, etc), including ion fluxes (Ca++), which are driven by atypical receptors. All in all, steroids affect cells through several different pathways and at least one atypical steroid receptor, none of which involve what most people consider the true “intracellular” mechanism of steroid action.