Abnormal Regulation of the Sympathetic Nervous System in α_2A-Adrenergic Receptor Knockout Mice

Abstract

alpha2-Adrenergic receptors (ARs) play a key role in regulating neurotransmitter release in the central and peripheral sympathetic nervous systems. To date, three subtypes of alpha2-ARs have been cloned (alpha2A, alpha2B, and alpha2C). Here we describe the physiological consequences of disrupting the gene for the alpha2A-AR. Mice lacking functional alpha2A subtypes were compared with wild-type (WT) mice, with animals lacking the alpha2B or alpha2C subtypes, and with mice carrying a point mutation in the alpha2A-AR gene (alpha2AD79N). Deletion of the alpha2A subtype led to an increase in sympathetic activity with resting tachycardia (knockout, 581 +/- 21 min-1; WT, 395 +/- 21 min-1), depletion of cardiac tissue norepinephrine concentration (knockout, 676 +/- 31 pg/mg protein; WT, 1178 +/- 98 pg/mg protein), and down-regulation of cardiac beta-ARs (Bmax: knockout, 23 +/- 1 fmol/mg protein; WT, 31 +/- 2 fmol/mg protein). The hypotensive effect of alpha2 agonists was completely absent in alpha2A-deficient mice. Presynaptic alpha2-AR function was tested in two isolated vas deferens preparations. The nonsubtype-selective alpha2 agonist dexmedetomidine completely blocked the contractile response to electrical stimulation in vas deferens from alpha2B-AR knockout, alpha2C-AR knockout, alpha2AD79N mutant, and WT mice. The maximal inhibition of vas deferens contraction by the alpha2 agonist in alpha2A-AR knockout mice was only 42 +/- 9%. [3H]Norepinephrine release studies performed in vas deferens confirmed these findings. The results indicate that the alpha2A-AR is a major presynaptic receptor subtype regulating norepinephrine release from sympathetic nerves; however, the residual alpha2-mediated effect in the alpha2A-AR knockout mice suggests that a second alpha2 subtype (alpha2B or alpha2C) also functions as a presynaptic autoreceptor to inhibit transmitter release.

Modulation of the baroreceptor reflex by α2A‐adrenoceptors: a study in α2A knockout mice

“…Animals were then placed in individual cages and allowed at least 4 h to recover from surgery. Preliminary experiments showed that extending the postsurgery period to 24 h did not change the cardiovascular parameters (unpublished results; compare also baseline values for mean arterial pressure and heart rate in the present study with Altman et al (1999) and Makaritsis et al (1999)). …”

“…Disruption of receptor genes represents a new tool to elucidate receptor mechanisms. Therefore, we used mice in which the gene encoding the a 2A -adrenoceptor had been disrupted (a 2A -KO; Altman et al, 1999;for review, see Hein, 2001). Mice sharing the genetic background of the a 2A -KO animals (wild type (WT)) were used as controls.…”

Activation of α2 Adrenergic Receptors Suppresses Fear Conditioning: Expression of c-Fos and Phosphorylated CREB in Mouse Amygdala

“…Wild-type C57BL/6J mice (Jackson Laboratories, Davis, CA), a 2A AR knockout (KO) adult male mice originated by Dr Brian Kobilka (Altman et al, 1999) and D79N mice originated by Dr Lee Limbird (MacMillan et al, 1996), which contains a point mutation that functionally inactivates the a 2A AR, were bred in house. Both were backcrossed onto a single C57BL/6J background.…”

Yohimbine impairs extinction of cocaine-conditioned place preference in an α2-adrenergic receptor independent process

“…Male ␣ 2A -AR KO mice were generated as previously described (Altman et al 1999) and backcrossed onto a C57BL/6J genetic background for a minimum of eight generations. KO and WT littermate controls were bred from heterozygous parents to minimize any potential genotype-related maternal abnormalities .…”