Preferential desensitization of beta- versus alpha 2-adrenergic receptors accelerates loss of response to norepinephrine in primary glial cultures.

The effect of norepinephrine (NE) on cAMP accumulation in primary glial cultures is mediated by two functionally opposing receptor subtypes. beta-Adrenergic receptor activation increases cAMP formation, whereas simultaneous alpha 2-adrenergic receptor activation partially inhibits this effect. We compared desensitization of these two responses during exposure to selective agonists or NE. Pretreatment with the beta-selective agonist isoproterenol (ISO) decreased responses to ISO, ISO plus the alpha 2-selective agonist UK 14,304 (UK), and NE. However, ISO plus UK and NE responses decreased more, relative to their control values, than did responses to ISO alone. Pretreatment with UK increased cAMP responses to both ISO and forskolin (sensitization), with little effect on alpha 2-mediated inhibition of these responses. Pretreatment with NE caused effects similar to those of both ISO and UK pretreatment. NE pretreatment decreased responses to ISO, ISO plus UK, and NE, sensitized responses to forskolin, and had little effect on alpha 2-mediated inhibition. Thus, chronic agonist exposure desensitizes beta-adrenergic receptors more rapidly and at much lower concentrations than alpha 2-adrenergic receptors in these cultures. The continuing alpha 2 inhibition during diminishing beta stimulation functionally accelerates the loss of the NE response.