Browsing Pathways

Dopamine agonists are chemical agents that bind to the dopamine receptors and activate cellular singling pathways. Dopamine receptors classify into two families based on their pharmacological, biochemical, and genetic properties: the D1-like dopamine receptor family includes D1 and D5 receptors, whereas the D2-like dopamine receptor family includes D2, D3, and D4 receptors. All dopamine receptors couple to G proteins. The D1 and D5 receptors couple to the Gs family of G proteins, and therefore an agonist binding to these receptors activate adenylyl cyclase and thus stimulates cAMP synthesis. The D2, D3, and D4 receptors couple to the Gi/o family of G proteins, and agonists inhibit adenylyl cyclase and thus cAMP synthesis. Increased intracellular cAMP activates protein kinase A, which phosphorylates many downstream protein targets, including 32-kDa dopamine and cAMP-regulated phosphoprotein (DARPP-32), ionotropic glutamate receptor, and GABA receptors. Because the DARPP-32 inhibits protein phosphatase 1, this phosphoprotein regulates the phosphorylation state and thus activity of various protein kinase A target proteins and neuronal activity. The D1 receptors are present on the smooth muscle of the renal, mesenteric, and coronary arteries and peripheral blood vessels in the skeletal muscle. Dopamine action on these receptors produces decreased blood pressure by reducing peripheral vascular resistance due to vasodilation. Dopamine agonists used to treat hypertensive emergencies do not show an affinity for D2 receptors.

Naturally occurring Endogenous compounds in mammals that naturally act like morphine in the opioid pathway include endorphins, enkephalins, and dynorphins. They are often referred to as endogenous opioids. They bind and activate opioid receptors mimicking the effects of opioid drugs like morphine. Endorphins are a group of endogenous opioid peptides that include beta-endorphin, alpha-endorphin, and gamma-endorphin. They are produced primarily in the pituitary gland and the hypothalamus in response to stress and pain. Endorphins bind to mu-opioid receptors and provide pain relief and a sense of well-being. They are sometimes referred to as "natural painkillers. Enkephalins are a class of endogenous opioid peptides that include met-enkephalin and leu-enkephalin. They are distributed widely in the central nervous system and peripheral tissues. Enkephalins bind to both delta-opioid and mu-opioid receptors and play a role in pain modulation, mood regulation, and other physiological functions. Dynorphins are another group of endogenous opioid peptides, with dynorphin A and dynorphin B being the most well-known. They primarily activate kappa-opioid receptors. Dynorphins are distributed throughout the brain and spinal cord and are involved in pain perception, stress responses, and mood regulation.

Muscle contractions occur when the myocyte is depolarized enough for an action potential to occur. Depolarization is caused by acetylcholine released from the adjacent motor neuron, which activates nicotinic acetylcholine receptors and opens the sodium/potassium channel. The fast influx of sodium and slow efflux of potassion trigger the action potential. This action potential activates L-type voltage-dependent calcium channels on the membrane and ryanodine receptors on the sarcoplasmic reticulum, both which cause calcium ions to be released into the cytosol. In smooth muscle, ionic calcium induces muscle contraction by binding to and activating myosin light chain kinase, while in striated muscle contraction results from ionic calcium binding to and activating troponin C.

Activation of the 5-HT2A and 5-HT2C receptors in the neurons typically leads to the activation of Gq proteins. Gq proteins stimulate phospholipase C (PLC), leading to the production of inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 induces calcium release from intracellular stores, leading to increased intracellular calcium levels. Increased intracellular calcium and DAG activation of protein kinase C (PKC) can lead to the modulation of various signaling pathways. The net effect on neuronal excitability can vary involving both excitatory and inhibitory influences depending on the context and the specific neuron, brain region and down stream signaling pathways involved. 5-HT2A receptor activation via Gq protein signaling can have excitatory effects in some neurons, particularly in the cerebral cortex and certain excitatory circuits. In the cortex, activation of 5-HT2A receptors can enhance neuronal excitability, synaptic transmission, and plasticity.

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. The nicotinic receptors are considered cholinergic receptors, since they respond to acetylcholine. Nicotinic receptors get their name from nicotine which does not stimulate the muscarinic acetylcholine receptors but selectively binds to the nicotinic receptors instead. As ionotropic receptors, nAChRs are directly linked to ion channels. New evidence suggests that these receptors can also use second messengers (as metabotropic receptors do) in some cases. Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors. Opening of the channel allows positively charged ions to move across it; in particular, sodium enters the cell and potassium exits. The net flow of positively charged ions is inward. The nAChR is a non-selective cation channel, meaning that several different positively charged ions can cross through. The activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movement of cations causes a depolarization of the plasma membrane (which results in an excitatory postsynaptic potential in neurons) leading to the activation of voltage-gated ion channels. On the other hand, the entry of calcium acts, either directly or indirectly, on different intracellular cascades. This leads, for example, to the regulation of activity of some genes or the release of neurotransmitters.