Alpha-1 adrenergic receptor

The alpha-1 'adrenergic receptor' is a G protein-coupled receptor associated with the G_q heterotrimeric G protein. It consists of three highly homologous subtypes, α_1A-, α_1B-, and α_1D-adrenergic. There is no α_1C receptor. At one time, there was a subtype known as α_1C, but it was found to be identical to the previously discovered α_1A receptor subtype. To avoid confusion, naming was continued with the letter D. Catecholamines like norepinephrine and epinephrine signal through the α₁-adrenergic receptors in the central and peripheral nervous systems. The crystal structure of the α_1B-adrenergic receptor subtype has been determined in complex with the inverse agonist -cyclazosin.

Effects

The α₁-adrenergic receptor has several general functions in common with the α₂-adrenergic receptor, but also has specific effects of its own. α₁-receptors primarily mediate smooth muscle contraction, but have important functions elsewhere as well. The neurotransmitter norepinephrine has higher affinity for the α₁ receptor than does the hormone adrenaline.

Smooth muscle

In smooth muscle cells of blood vessels the principal effect of activation of these receptors is vasoconstriction. Blood vessels with α₁-adrenergic receptors are present in the skin, the sphincters of gastrointestinal system, kidney and brain. During the fight-or-flight response vasoconstriction results in decreased blood flow to these organs. This accounts for the pale appearance of the skin of an individual when frightened.
It also induces contraction of the internal urethral sphincter of the urinary bladder, although this effect is minor compared to the relaxing effect of β₂-adrenergic receptors. In other words, the overall effect of sympathetic stimuli on the bladder is relaxation, in order to inhibit micturition upon anticipation of a stressful event. Other effects on smooth muscle are contraction in:

Ureter
Uterus : this is minor compared to the relaxing effects of the β₂ receptor, agonists of whichnotably albuterol/salbutamolwere formerly used to inhibit premature labor.
Urethral sphincter
Bronchioles
Iris dilator muscle
Seminal tract, resulting in ejaculation
Neuronal

Activation of α₁-adrenergic receptors produces anorexia and partially mediates the efficacy of appetite suppressants like phenylpropanolamine and amphetamine in the treatment of obesity. Norepinephrine has been shown to decrease cellular excitability in all layers of the temporal cortex, including the primary auditory cortex. In particular, norepinephrine decreases glutamatergic excitatory postsynaptic potentials by the activation of α₁-adrenergic receptors. Norepinephrine also stimulates serotonin release by binding α₁-adrenergic receptors located on serotonergic neurons in the raphe.
α₁-adrenergic receptor subtypes increase inhibition in the olfactory system, suggesting a synaptic mechanism for noradrenergic modulation of olfactory driven behaviors.

Other

Both positive and negative inotropic effects on heart muscle
Secretion from salivary gland
Increase salivary potassium levels
Glycogenolysis and gluconeogenesis in liver.
Secretion from sweat glands
Contraction of the urinary bladder urothelium and lamina propria
Na⁺ reabsorption from kidney
* Stimulate proximal tubule NHE3
* Stimulate proximal tubule basolateral Na-K ATPase
Activate mitogenic responses and regulate growth and proliferation of many cells
Involved in the detection of mechanical feedback on the hypoglossal motor neurons which allow a long-term facilitation in respiration in response to repeated apneas.
Signaling cascade

α₁-Adrenergic receptors are members of the G protein-coupled receptor superfamily. Upon activation, a heterotrimeric G protein, G_q, activates phospholipase C, which causes phosphatidylinositol to be transformed into inositol trisphosphate (IP₃) and diacylglycerol (DAG). While DAG stays near the membrane, IP₃ diffuses into the cytosol and to find the IP₃ receptor on the endoplasmic reticulum, triggering calcium release from the stores. This triggers further effects, primarily through the activation of an enzyme Protein Kinase C. This enzyme, as a kinase, functions by phosphorylation of other enzymes causing their activation, or by phosphorylation of certain channels leading to the increase or decrease of electrolyte transfer in or out of the cell.

Activity during exercise

During exercise, α₁-adrenergic receptors in active muscles are attenuated in an exercise intensity-dependent manner, allowing the β₂-adrenergic receptors which mediate vasodilation to dominate. In contrast to α₂-adrenergic receptors, α₁-adrenergic-receptors in the arterial vasculature of skeletal muscle are more resistant to inhibition, and attenuation of α1-adrenergic-receptor-mediated vasoconstriction only occurs during heavy exercise.
Note that only active muscle α₁-adrenergic receptors will be blocked. Resting muscle will not have its α₁-adrenergic receptors blocked, and hence the overall effect will be α₁-adrenergic-mediated vasoconstriction.

Ligands

; Agonists

; Antagonists

Various heterocyclic antidepressants and antipsychotics are α₁-adrenergic receptor antagonists as well. This action is generally undesirable in such agents and mediates side effects like orthostatic hypotension, and headaches due to excessive vasodilation.